Cephalometric analysis performance discrepancy between orthodontists and an artificial intelligence model using lateral cephalometric radiographs.

PURPOSE: The purpose of the present clinical study was to compare the Ricketts and Steiner cephalometric analysis obtained by two experienced orthodontists and artificial intelligence (AI)-based software program and measure the orthodontist variability. MATERIALS AND METHODS: A total of 50 lateral cephalometric radiographs from 50 patients were obtained. Two groups were created depending on the operator performing the cephalometric analysis: orthodontists (Orthod group) and an AI software program (AI group). In the Orthod group, two independent experienced orthodontists performed the measurements by performing a manual identification of the cephalometric landmarks and a software program (NemoCeph; Nemotec) to calculate the measurements. In the AI group, an AI software program (CephX; ORCA Dental AI) was selected for both the automatic landmark identification and cephalometric measurements. The Ricketts and Steiner cephalometric analyses were assessed in both groups including a total of 24 measurements. The Shapiro-Wilk test showed that the data was normally distributed. The t-test was used to analyze the data (α = 0.05). RESULTS: The t-test analysis showed significant measurement discrepancies between the Orthod and AI group in seven of the 24 cephalometric parameters tested, namely the corpus length (p = 0.003), mandibular arc (p < 0.001), lower face height (p = 0.005), overjet (p = 0.019), and overbite (p = 0.022) in the Ricketts cephalometric analysis and occlusal to SN (p = 0.002) and GoGn-SN (p < 0.001) in the Steiner cephalometric analysis. The intraclass correlation coefficient (ICC) between both orthodontists of the Orthod group for each cephalometric measurement was calculated. CONCLUSIONS: Significant discrepancies were found in seven of the 24 cephalometric measurements tested between the orthodontists and the AI-based program assessed. The intra-operator reliability analysis showed reproducible measurements between both orthodontists, except for the corpus length measurement. CLINICAL SIGNIFICANCE: The artificial intelligence software program tested has the potential to automatically obtain cephalometric analysis using lateral cephalometric radiographs; however, additional studies are needed to further evaluate the accuracy of this AI-based system.

Differences in Expression of IQSEC2 Transcript Isoforms in Male and Female Cases with Loss of Function Variants and Neurodevelopmental Disorder.

Pathogenic hemizygous or heterozygous mutations in the IQSEC2 gene cause X-linked intellectual developmental disorder-1 (XLID1), characterized by a variable phenotype including developmental delay, intellectual disability, epilepsy, hypotonia, autism, microcephaly and stereotypies. It affects both males and females typically through loss of function in males and haploinsufficiency in heterozygous females. Females are generally less affected than males. Two novel unrelated cases, one male and one female, with de novo IQSEC2 variants were detected by trio-based whole exome sequencing. The female case had a previously undescribed frameshift mutation (NM_001111125:c.3300dup; p.Met1101Tyrfs*5), and the male showed an intronic variant in intron 6, with a previously unknown effect (NM_001111125:c.2459+21C>T). IQSEC2 gene expression study revealed that this intronic variant created an alternative donor splicing site and an aberrant product, with the inclusion of 19bp, confirming the pathogenic effect of the intron variant. Moreover, a strong reduction in the expression of the long, but also the short IQSEC2 isoforms, was detected in the male correlating with a more severe phenotype, while the female case showed no decreased expression of the short isoform, and milder effects of the disease. This suggests that the abnormal expression levels of the different IQSEC2 transcripts could be implicated in the severity of disease manifestations.

The role of exosomes on colorectal cancer: A review.

Exosomes are extracellular microvesicles released from cells, which are involved in many biological and pathological processes, mainly because of their role in intercellular communication. Exosomes derived from colorectal cancer (CRC) cells are related to oncogenesis, tumor cell survival, chemo-resistance, and metastasis. The role of the exosomes in these processes involves the transfer of proteins, RNAs, or mutant versions of proto-oncogenes to the target cells. In recent years, great efforts have been made to identify useful biomarkers in CRC exosomes for diagnosis, prediction of prognosis, and treatment response. This review focuses on recent studies on CRC exosomes, considering isolation, cargo, biomarkers, and the effects of exosomes on the development and progression of CRC, including resistance to antitumor therapy.

Effectiveness and safety of moderate-intensity aerobic water exercise during pregnancy for reducing use of epidural analgesia during labor: protocol for a randomized clinical trial.

BACKGROUND: Epidural analgesia during labor can provide effective pain relief, but can also lead to adverse effects. The practice of moderate exercise during pregnancy is associated with an increased level of endorphins in the blood, and this could also provide pain relief during labor. Aerobic water exercises, rather than other forms of exercise, do not negatively impact articulations, reduce edema, blood pressure, and back pain, and increase diuresis. We propose a randomized controlled trial (RCT) to evaluate the effectiveness and safety of a moderate water exercise program during pregnancy on the need for epidural analgesia during labor. METHODS: A multi-center, parallel, randomized, evaluator blinded, controlled trial in a primary care setting. We will randomised 320 pregnant women (14 to 20 weeks gestation) who have low risk of complications to a moderate water exercise program or usual care. DISCUSSION: The findings of this research will contribute toward understanding of the effects of a physical exercise program on pain and the need for analgesia during labor. TRIAL REGISTRATION: ISRCTN Registry identifier: 14097513 register on 04 September 2017. Retrospectively registered.

Remediation therapy in patients with alcohol use disorders and neurocognitive disorders: A Pilot Study. / Terapia de rehabilitación cognitiva en pacientes con trastorno por consumo de alcohol y trastorno neurocognitivo. Estudio piloto.

Many alcohol-dependent patients suffer from cognitive impairment of variable severity, manifested by alterations in retrograde and anterograde memory, visuospatial processing, cognitive abilities and attention, some of which are reversible. In this context, cognitive remediation therapies could significantly improve patients' performance; therefore, these are considered a valuable alternative. The aim of this study was to implement cognitive remediation therapy in patients with alcohol dependence and cognitive impairment and evaluate its viability and effectiveness. The participants were sixteen abstinent, alcohol-dependent patients (mean age of 59 years, 63% males) from the Addictive Behaviours Unit of a tertiary hospital. Over 6 months, a nurse led 1-hour weekly sessions (24 sessions in total) during which exercises for improving functional, social and cognitive performance were completed. Patients were assessed at baseline, at the end of the study and 6 months later, using the Mini-Mental State Examination (MMSE) and the Memory Alteration Test (M@T). Their respective scores were 26.4 (SD 3.16), 29 (SD 1.67) and 27 (SD 3.1) for the MMSE and 38.7 (SD 6.81), 45.7 (SD 5.6) and 41.1 (SD 7.86) for the M@T. Changes were assessed with both Friedman and Wilcoxon signed-rank tests, with mostly statistically significant differences (p < 0.05). Assistance and satisfaction were high. Therefore, the therapy was viable, widely accepted and effective.

El deterioro cognitivo es común en los pacientes alcohólicos. Éste se manifiesta por alteraciones en la memoria anterógrada y retrógrada, el procesamiento visual-espacial, y en las habilidades cognitivas y la atención, siendo algunas reversibles. Las terapias de rehabilitación cognitiva podrían mejorar el rendimiento de los pacientes, siendo una alternativa terapéutica de interés. El objetivo de este estudio piloto fue evaluar la implementación, viabilidad y efectividad de la terapia de rehabilitación cognitiva en pacientes con dependencia al alcohol y deterioro cognitivo asociado. Se trata de un estudio piloto con 16 pacientes (63% hombres, edad media de 59 años) seguidos en la Unidad de Conductas Adictivas de un hospital de tercer nivel. Siendo la abstinencia un requisito para la inclusión, durante 6 meses una enfermera realizó sesiones semanales de una hora (24 sesiones), realizándose ejercicios de psico-estimulación para la mejora del rendimiento cognitivo, funcional y social. Se evaluó a los pacientes al inicio, al final y pasados 6 meses, mediante las escalas MMSE (test Mini-mental de Lobo) y T@M (test de Alteración de Memoria). Sus puntuaciones medias respectivas fueron 26.4 (DE 3,16), 29 (DE 1,67) y 27 (DE 3,1) para MMSE y 38,7 (DE 6,81), 45,7 (DE 5,6) y 41,1 (DE 7,86) para T@M. Los datos se analizaron mediante la prueba de Friedman y se comparon los distintos periodos temporales mediante la prueba de rangos con signo de Wilcoxon, siendo la mayoría de comparaciones significativas (p < 0,05). La asistencia y la satisfacción fueron elevadas. Así pues, la terapia fue viable, ampliamente aceptada y mostró ser efectiva.

Adherence to reduced-polluting biomass fuel stoves improves respiratory and sleep symptoms in children.

BACKGROUND: Symptoms of sleep apnea are markedly increased in children exposed to smoke from biomass fuels and are reduced by kitchen stoves that improve indoor biomass pollution. However, the impact of adherence to the use of improved stoves has not been critically examined. METHODS: Sleep-related symptom questionnaires were obtained from children <15 years of age in 56 families residing in the communities of Lliupapuquio, Andahuaylas province in Peru before and 2 years after installation of less-polluting Inkawasi cooking stoves. RESULTS: 82 children with lifetime exposures to indoor fuel pollution were included. When compared to those alternating between both types of stoves or those using traditional stoves only, those children who exclusively used Inkawasi cooking stoves showed significant improvements in sleep and respiratory related symptoms, but some minor albeit significant improvements occurred when both stoves were concomitantly used. CONCLUSIONS: Improvements in respiratory and sleep-related symptoms associated with elevated indoor biomass pollution occur only following implementation and exclusive utilization of improved kitchen stoves.

ALK Inhibition With Alectinib for Refractory Metastatic Renal Cell Carcinoma With ALK Rearrangement: A Rare Case Report and Literature Review.

ALK-rearranged RCC refractory to several lines of treatment has a durable response when treated with alectinib.

Acne Keloidalis Nuchae: A Multicenter Retrospective Study of 142 Hispanic Patients.

INTRODUCTION: Acne keloidalis nuchae (AKN) is a primary cicatricial alopecia with mixed infiltrate. It is more common in Africans or persons of African descent. OBJECTIVES: Our objective was to describe the epidemiology and clinical and trichoscopic presentations of AKN in a large series of Hispanic patients. METHODS: This was a retrospective study from 10 different dermatological centers in Argentina, Colombia, Mexico, and Peru. Patients with a clinical diagnosis of AKN treated by 12 dermatologists experienced in trichology from 2018 to 2022 were included. The Umar classification system was used to determine severity. RESULTS: We identified 142 patients with AKN: 98% were male (n=140) with a mean age of 32 years; 108 patients had a previous history of trauma to the nuchal area (76%, P < 0.001); and 48 were positive for a history of acne (33.8%, P = 0.021). Patients with >50 months of evolution were mainly classified in classes III and IV compared to patients with an evolution of <50 months (30%, n=9 vs. 14%, n=15; P = 0.019; respectively). CONCLUSION: AKN should be considered in the differential diagnosis in the Hispanic population. Advanced stages of the disease are correlated with chronic evolution.

Micellar liquid chromatography as a sustainable tool to quantify three statins in oral solid dosage forms.

A method based on micellar liquid chromatography has been developed to determine rosuvastatin, lovastatin and simvastatin in oral solid dosage forms. Samples were solved in mobile phase up to the target concentration, filtered and directly injected. The three statins were resolved in 30 min, using an aqueous solution of 0.10 M sodium dodecyl sulfate - 7.0% 1-butanol, buffered at pH 3 with 0.01 M phosphate salt as mobile phase, running under isocratic mode at 1 mL/min through a C18 column. Detection was at 240 nm. The effect of sodium dodecyl sulfate on elution strength was more important than that of the organic solvent. The procedure was successfully validated by the guidelines of the International Council for Harmonization in terms of: specificity, linearity (r2 > 0.990), calibration range (1.5 - 15 mg/L for rosuvastatin, 0.5-10 mg/L for lovastatin and simvastatin), limit of detection (0.4, 0.2 and 0.15 mg/L for rosuvastatin, lovastatin and simvastatin, respectively), trueness (98.8-101.7%), precision (<2.7%), carry-over effect, robustness, and stability. Values were inside the acceptance criteria of the Methods, Method Verification and Validation, Food and Drug Administration-Office of Regulatory Affairs, thus ensuring the reliability of the results. The main feature was the low proportion of organic solvent used, thus making the procedure sustainable and green. Besides, it was easy-to-conduct and with high sample-throughput, and then useful for routine analysis in pharmaceutical quality control. Finally, it was applied to commercial pharmaceutical preparations.

The Potential Revolution of Cancer Treatment with CRISPR Technology.

Immuno-oncology (IO) and targeted therapies, such as small molecule inhibitors, have changed the landscape of cancer treatment and prognosis; however, durable responses have been difficult to achieve due to tumor heterogeneity, development of drug resistance, and adverse effects that limit dosing and prolonged drug use. To improve upon the current medicinal armamentarium, there is an urgent need for new ways to understand, reverse, and treat carcinogenesis. Clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein (Cas) 9 is a powerful and efficient tool for genome editing that has shown significant promise for developing new therapeutics. While CRISPR/Cas9 has been successfully used for pre-clinical cancer research, its use in the clinical setting is still in an early stage of development. The purpose of this review is to describe the CRISPR technology and to provide an overview of its current applications and future potential as cancer therapies.

Construction and Evaluation of a Realistic Low-Cost Model for Training in Chest-Tube Insertion.

INTRODUCTION: Emergency thoracostomy is applied in life-threatening situations. Simulation plays a pivotal role in training in invasive techniques used mainly in stressful situations. Currently available commercial simulation models for thoracostomy have various drawbacks. METHODS: We designed a thoracostomy phantom from discarded hospital materials and pigskin with underlying flesh. The phantom can be used alone for developing technical skills or mounted on an actor in simulation scenarios. Medical students, intensive care unit (ICU) and emergency department teams, and thoracostomy experts evaluated its technical fidelity and usefulness for achieving learning objectives in workshops. RESULTS: The materials used to construct the phantom cost €47. A total of 12 experts in chest-tube placement and 73 workshop participants (12 ICU physicians and nurses, 20 emergency physicians and nurses, and 41 fourth-year medical students) evaluated the model. All groups rated the model's usefulness and the sensation of perforating the pleura highly. Experts rated the air release after pleura perforation lower than other groups. Lung reexpansion was the lowest rated item in all groups. Ratings of the appearance and feel of the model correlated strongly among all groups and experts. The ICU professionals rated the resistance encountered in introducing the chest drain lower than the other groups. CONCLUSIONS: This low-cost, reusable, transportable, and highly realistic model is an attractive alternative to commercial models for training in chest-tube insertion skills.

Stress-induced sensitization to cocaine: actin cytoskeleton remodeling within mesocorticolimbic nuclei.

This study investigated the consequence of repeated stress on actin cytoskeleton remodeling in the nucleus accumbens (NAc) and prefrontal cortex (Pfc), and the involvement of this remodeling in the expression of stress-induced motor cross-sensitization with cocaine. Wistar rats were restrained daily (2 h) for 7 days and, 3 weeks later, their NAc and Pfc were dissected 45 min after acute saline or cocaine (30 mg/kg i.p.). F-actin, actin-binding proteins (ABP) and GluR1 were quantified by Western blotting, and dendritic spines and postsynaptic density (PSD) size measured by electron microscopy. In the NAc from the stress plus cocaine group we observed a decrease in the phosphorylation of two ABPs, cofilin and cortactin, and an increase in the PSD size and the surface expression of GluR1, consistent with a more highly branched actin cytoskeleton. The Pfc also showed evidence of increased actin polymerization after stress as an increase was observed in Arp2, and in the number of spines. Inhibiting actin cycling and polymerization with latrunculin A into the NAc, but not the Pfc, inhibited the expression of cross-sensitization to cocaine (15 mg/kg i.p.) and restored the expression of GluR1 to control levels. This study shows that a history of repeated stress alters the ability of a subsequent cocaine injection to modulate dendritic spine morphology, actin dynamics and GluR1 expression in the NAc. Furthermore, by regulating GluR1 expression in the NAc, elevated actin cycling contributes to the expression of cross-sensitization between stress and cocaine, while stress-induced changes in the Pfc were not associated with cross-sensitization.

SOX9 Triggers Different Epithelial to Mesenchymal Transition States to Promote Pancreatic Cancer Progression.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers mainly due to spatial obstacles to complete resection, early metastasis and therapy resistance. The molecular events accompanying PDAC progression remain poorly understood. SOX9 is required for maintaining the pancreatic ductal identity and it is involved in the initiation of pancreatic cancer. In addition, SOX9 is a transcription factor linked to stem cell activity and is commonly overexpressed in solid cancers. It cooperates with Snail/Slug to induce epithelial-mesenchymal transition (EMT) during neural development and in diseases such as organ fibrosis or different types of cancer. METHODS: We investigated the roles of SOX9 in pancreatic tumor cell plasticity, metastatic dissemination and chemoresistance using pancreatic cancer cell lines as well as mouse embryo fibroblasts. In addition, we characterized the clinical relevance of SOX9 in pancreatic cancer using human biopsies. RESULTS: Gain- and loss-of-function of SOX9 in PDAC cells revealed that high levels of SOX9 increased migration and invasion, and promoted EMT and metastatic dissemination, whilst SOX9 silencing resulted in metastasis inhibition, along with a phenotypic reversion to epithelial features and loss of stemness potential. In both contexts, EMT factors were not altered. Moreover, high levels of SOX9 promoted resistance to gemcitabine. In contrast, overexpression of SOX9 was sufficient to promote metastatic potential in K-Ras transformed MEFs, triggering EMT associated with Snail/Slug activity. In clinical samples, SOX9 expression was analyzed in 198 PDAC cases by immunohistochemistry and in 53 patient derived xenografts (PDXs). SOX9 was overexpressed in primary adenocarcinomas and particularly in metastases. Notably, SOX9 expression correlated with high vimentin and low E-cadherin expression. CONCLUSIONS: Our results indicate that SOX9 facilitates PDAC progression and metastasis by triggering stemness and EMT.

MTAP deficiency creates an exploitable target for antifolate therapy in 9p21-loss cancers.

Methylthioadenosine phosphorylase, an essential enzyme for the adenine salvage pathway, is often deficient (MTAPdef) in tumors with 9p21 loss and hypothetically renders tumors susceptible to synthetic lethality by antifolates targeting de novo purine synthesis. Here we report our single arm phase II trial (NCT02693717) that assesses pemetrexed in MTAPdef urothelial carcinoma (UC) with the primary endpoint of overall response rate (ORR). Three of 7 enrolled MTAPdef patients show response to pemetrexed (ORR 43%). Furthermore, a historic cohort shows 4 of 4 MTAPdef patients respond to pemetrexed as compared to 1 of 10 MTAP-proficient patients. In vitro and in vivo preclinical data using UC cell lines demonstrate increased sensitivity to pemetrexed by inducing DNA damage, and distorting nucleotide pools. In addition, MTAP-knockdown increases sensitivity to pemetrexed. Furthermore, in a lung adenocarcinoma retrospective cohort (N = 72) from the published BATTLE2 clinical trial (NCT01248247), MTAPdef associates with an improved response rate to pemetrexed. Our data demonstrate a synthetic lethal interaction between MTAPdef and de novo purine inhibition, which represents a promising therapeutic strategy for larger prospective trials.

Hydroxychloroquine / azithromycin in COVID-19: The association between time to treatment and case fatality rate.

BACKGROUND: Currently, there is no formally accepted pharmacological treatment for COVID-19. MATERIALS AND METHODS: We included COVID-19 outpatients of a Peruvian primary care center from Lima, Peru, who were treated between April 30 - September 30, 2020, with hydroxychloroquine and azithromycin. Logistic regression was applied to determine factors associated with case-fatality rate. RESULTS: A total of 1265 COVID-19 patients with an average age of 44.5 years were studied. Women represented 50.1% of patients, with an overall 5.9 symptom days, SpO2 97%, temperature of 37.3 °C, 41% with at least one comorbidity and 96.1% one symptom or sign. No patient treated within the first 72 h of illness died. The factors associated with higher case fatality rate were age (OR = 1.06; 95% CI 1.01-1.11, p = 0.021), SpO2 (OR = 0.87; 95% CI 0.79-0.96, p = 0.005) and treatment onset (OR = 1.16; 95% CI 1.06-1.27, p = 0.002), being the latter the only associated in the multivariate analysis (OR = 1.18; 95% CI 1.05-1.32, p = 0.005). 0.6% of our patients died. CONCLUSIONS: The case fatality rate in COVID-19 outpatients treated with hydroxychloroquine/azithromycin was associated with the number of days of illness on which treatment was started.

Frequency of depression and quality of life in patients with diabetes mellitus in public health facilities in Metropolitan Lima.

INTRODUCTION: Diabetes is one of the main pandemics in recent years. Its association with depression increases the risk of mortality and morbidity. The coexistence of both diseases leads to poor management of diabetes, which leads to a worse quality of life. OBJECTIVE: To determine the frequency of depression in patients with diabetes mellitus and the effect of both pathologies on the quality of life in patients who attend outpatient appointments at public health facilities in Lima and Callao. METHODOLOGY: Secondary analysis of the Epidemiological Study of Mental Health of depression in diabetic adults. The instrument used to determine the depressive episode was the MINI (Mini-International Neuropsychiatric Interview) while quality of life was measured using the Mezzich Quality of Life Index. Diagnosis information of type 1 or 2 diabetes was obtained from the daily medical record (HIS) of care. RESULTS: The frequency of depression in the 471 patients with diabetes was 5.8% in the last two weeks. While the annual frequency was 8.6% and 31.8% at some point in life. Being a woman was associated with a greater frequency of depression. Quality of life was lower in patients with diabetes and depression (p < 0.005). CONCLUSIONS: The frequency of depression in patients with diabetes who are treated on an outpatient basis in public health centres is higher than the general population and their quality of life is significantly reduced, which raises the need for considering depression as an additional factor to the burden of morbidity of this condition.

Acute Altitude Acclimatization in Young Healthy Volunteers: Nocturnal Oxygenation Increases Over Time, Whereas Periodic Breathing Persists.

Ju, Jia-Der, Cristian Zhang, Francis P. Sgambati, Lidia M. Lopez, Luu V. Pham, Alan R. Schwartz, and Roberto A. Accinelli. Acute altitude acclimatization in young healthy volunteers: nocturnal oxygenation increases over time whereas periodic breathing persists. High Alt Med Biol. 22:14-23, 2021. Study Objectives: This study aimed to examine the acute effects of high altitude (HA) on sleep disordered breathing (sleep apnea and nocturnal hypoxemia) and acute mountain sickness and to characterize acclimatization over time. Methods: Ten native lowlanders residing at sea level (SL) completed the Lake Louise Score (LLS) and underwent nocturnal polygraphy (ApneaLink Plus) for nine consecutive nights (N1-N9) at HA (2,761 m) and two nights before and after HA. Nocturnal oxygen profiles were assessed by measuring the mean nocturnal oxyhemoglobin saturation (SpO2) during sleep, and sleep apnea severity as assessed by measuring the Apnea-Hypopnea Index (AHI). Mixed-effects linear regression was used to model responses in outcomes (mean nocturnal SpO2, logAHI, and LLS) between HA and SL. Changes in SpO2 and AHI were examined in subgroups with mild versus marked nocturnal SpO2 and low versus high AHI during exposure to HA and compared between subgroups. Results: Compared with SL, the mean nocturnal SpO2 was lower (p < 0.0001) and AHI was higher (p < 0.0001) at HA. The mean nocturnal SpO2 increased progressively (p < 0.001), whereas AHI remained high (p < 0.978) and relatively unchanged over nine successive nights at HA. Those with markedly reduced SpO2 upon arrival at HA exhibited progressive increases in the mean nocturnal SpO2 over time at HA compared with those with mild nocturnal desaturation. LLS rose at HA, but no differences were observed between subgroups. Conclusions: In healthy HA sojourners, the mean nocturnal SpO2 increased progressively over time, whereas AHI remained elevated, suggesting distinctive phenotypes and acclimatization responses to HA.

Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of urothelial cancer.

A number of immunotherapies have been developed and adopted for the treatment of urothelial cancer (encompassing cancers arising from the bladder, urethra, or renal pelvis). For these immunotherapies to positively impact patient outcomes, optimal selection of agents and treatment scheduling, especially in conjunction with existing treatment paradigms, is paramount. Immunotherapies also warrant specific and unique considerations regarding patient management, emphasizing both the prompt identification and treatment of potential toxicities. In order to address these issues, the Society for Immunotherapy of Cancer (SITC) convened a panel of experts in the field of immunotherapy for urothelial cancer. The expert panel developed this clinical practice guideline (CPG) to inform healthcare professionals on important aspects of immunotherapeutic treatment for urothelial cancer, including diagnostic testing, treatment planning, immune-related adverse events (irAEs), and patient quality of life (QOL) considerations. The evidence- and consensus-based recommendations in this CPG are intended to give guidance to cancer care providers treating patients with urothelial cancer.

Evaluation of Technology-Enabled Monitoring of Patient-Reported Outcomes to Detect and Treat Toxic Effects Linked to Immune Checkpoint Inhibitors.

Importance: Immune checkpoint inhibitors can produce distinct toxic effects that require prompt recognition and timely management. Objective: To develop a technology-enabled, dynamically adaptive protocol that can provide the accurate information needed to inform specific remedies for immune toxic effects in patients treated with immune checkpoint inhibitors. Design, Setting, and Participants: An open-label cohort study was conducted at a single tertiary referral center from September 6, 2019, to September 3, 2020. The median follow-up duration was 63 (interquartile range, 35.5-122) days. Fifty patients with genitourinary cancers treated with immune checkpoint inhibitors were enrolled. Interventions: A fit-for-purpose electronic platform was developed to enable active patient and care team participation. A smartphone application downloaded onto patients' personal mobile devices prompted them to report their symptoms at least 3 times per week. The set of symptoms and associated queries were paired with alert thresholds for symptoms requiring clinical action. Main Outcomes and Measures: The primary end point of this interim analysis was feasibility, as measured by patient and care team adherence, and lack of increase in care team staffing. Operating characteristics were estimated for each symptom alert and used to dynamically adapt the alert thresholds to ensure sensitivity while reducing unnecessary alerts. Results: Of the 50 patients enrolled, 47 had at least 1 follow-up visit and were included in the analysis. Median age was 65 years (range, 37-86), 39 patients (83%) were men, and 39 patients (83%) had metastatic cancer, with the most common being urothelial cell carcinoma and renal cell carcinoma (22 [47%] patients each). After initial onboarding, no further care team training or additional care team staffing was required. Patients had a median study adherence rate of 74% (interquartile range, 60%-86%) and 73% of automated alerts were reviewed within 3 days by the clinic team. Symptoms with the highest positive predictive value for adverse events requiring acute intervention included dizziness (21%), nausea/vomiting (26%), and shortness of breath (14%). The symptoms most likely to result in unnecessary alerts were arthralgia and myalgia, fatigue, and cough. Conclusions and Relevance: The findings of this cohort study suggest an acceptable and fiscally sound method can be developed to create a dynamic learning system to detect and manage immune-related toxic effects.