Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease.

Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels. Emerging evidence suggests that ferroptosis represents an ancient vulnerability caused by the incorporation of polyunsaturated fatty acids into cellular membranes, and cells have developed complex systems that exploit and defend against this vulnerability in different contexts. The sensitivity to ferroptosis is tightly linked to numerous biological processes, including amino acid, iron, and polyunsaturated fatty acid metabolism, and the biosynthesis of glutathione, phospholipids, NADPH, and coenzyme Q10. Ferroptosis has been implicated in the pathological cell death associated with degenerative diseases (i.e., Alzheimer's, Huntington's, and Parkinson's diseases), carcinogenesis, stroke, intracerebral hemorrhage, traumatic brain injury, ischemia-reperfusion injury, and kidney degeneration in mammals and is also implicated in heat stress in plants. Ferroptosis may also have a tumor-suppressor function that could be harnessed for cancer therapy. This Primer reviews the mechanisms underlying ferroptosis, highlights connections to other areas of biology and medicine, and recommends tools and guidelines for studying this emerging form of regulated cell death.

Precision Tumor Recognition by T Cells With Combinatorial Antigen-Sensing Circuits.

T cells can be re-directed to kill cancer cells using chimeric antigen receptors (CARs) or T cell receptors (TCRs). This approach, however, is constrained by the rarity of tumor-specific single antigens. Targeting antigens also found on bystander tissues can cause life-threatening adverse effects. A powerful way to enhance ON-target activity of therapeutic T cells is to engineer them to require combinatorial antigens. Here, we engineer a combinatorially activated T cell circuit in which a synthetic Notch receptor for one antigen induces the expression of a CAR for a second antigen. These dual-receptor AND-gate T cells are only armed and activated in the presence of dual antigen tumor cells. These T cells show precise therapeutic discrimination in vivo-sparing single antigen "bystander" tumors while efficiently clearing combinatorial antigen "disease" tumors. This type of precision dual-receptor circuit opens the door to immune recognition of a wider range of tumors. VIDEO ABSTRACT.

Dynamic imaging of genomic loci in living human cells by an optimized CRISPR/Cas system.

The spatiotemporal organization and dynamics of chromatin play critical roles in regulating genome function. However, visualizing specific, endogenous genomic loci remains challenging in living cells. Here, we demonstrate such an imaging technique by repurposing the bacterial CRISPR/Cas system. Using an EGFP-tagged endonuclease-deficient Cas9 protein and a structurally optimized small guide (sg) RNA, we show robust imaging of repetitive elements in telomeres and coding genes in living cells. Furthermore, an array of sgRNAs tiling along the target locus enables the visualization of nonrepetitive genomic sequences. Using this method, we have studied telomere dynamics during elongation or disruption, the subnuclear localization of the MUC4 loci, the cohesion of replicated MUC4 loci on sister chromatids, and their dynamic behaviors during mitosis. This CRISPR imaging tool has potential to significantly improve the capacity to study the conformation and dynamics of native chromosomes in living human cells.

Dysregulated 24 h melatonin secretion associated with intrinsically photosensitive retinal ganglion cell function in diabetic retinopathy: a cross-sectional study.

AIMS/HYPOTHESIS: The aim of this study was to explore whether diabetic retinopathy is associated with alterations of the circadian system, and to examine the role of reduced intrinsically photosensitive retinal ganglion cell (ipRGC) function. METHODS: Participants with type 2 diabetes, with diabetic retinopathy (n=14) and without diabetic retinopathy (n=9) underwent 24 h blood sampling for melatonin and cortisol under controlled laboratory conditions. ipRGC function was inferred from the post-illumination pupil response (PIPR). Habitual sleep duration, efficiency and variability were assessed by actigraphy. RESULTS: Participants with diabetic retinopathy compared to participants without diabetic retinopathy had smaller PIPR (p=0.007), lower 24 h serum melatonin output (p=0.042) and greater day-to-day sleep variability (p=0.012). By contrast, 24 h cortisol profiles, sleep duration and efficiency were similar in both groups. Six individuals with diabetic retinopathy had no detectable dim-light melatonin onset. PIPR correlated with 24 h mean melatonin levels (r=0.555, p=0.007). CONCLUSIONS/INTERPRETATION: ipRCG dysfunction in diabetic retinopathy is associated with disruptions of the 24 h melatonin rhythm, suggesting circadian dysregulation in diabetic retinopathy.

Identification of Glucose Transport Modulators In Vitro and Method for Their Deep Learning Neural Network Behavioral Evaluation in Glucose Transporter 1-Deficient Mice.

Metabolic flux augmentation via glucose transport activation may be desirable in glucose transporter 1 (Glut1) deficiency syndrome (G1D) and dementia, whereas suppression might prove useful in cancer. Using lung adenocarcinoma cells that predominantly express Glut1 relative to other glucose transporters, we screened 9,646 compounds for effects on the accumulation of an extracellularly applied fluorescent glucose analog. Five drugs currently prescribed for unrelated indications or preclinically characterized robustly enhanced intracellular fluorescence. Additionally identified were 37 novel activating and nine inhibitory compounds lacking previous biologic characterization. Because few glucose-related mechanistic or pharmacological studies were available for these compounds, we developed a method to quantify G1D mouse behavior to infer potential therapeutic value. To this end, we designed a five-track apparatus to record and evaluate spontaneous locomotion videos. We applied this to a G1D mouse model that replicates the ataxia and other manifestations cardinal to the human disorder. Because the first two drugs that we examined in this manner (baclofen and acetazolamide) exerted various impacts on several gait aspects, we used deep learning neural networks to more comprehensively assess drug effects. Using this method, 49 locomotor parameters differentiated G1D from control mice. Thus, we used parameter modifiability to quantify efficacy on gait. We tested this by measuring the effects of saline as control and glucose as G1D therapy. The results indicate that this in vivo approach can estimate preclinical suitability from the perspective of G1D locomotion. This justifies the use of this method to evaluate our drugs or other interventions and sort candidates for further investigation. SIGNIFICANCE STATEMENT: There are few or no activators and few clinical inhibitors of glucose transport. Using Glut1-rich cells exposed to a glucose analog, we identified, in highthroughput fashion, a series of novel modulators. Some were drugs used to modify unrelated processes and some represented large but little studied chemical compound families. To facilitate their preclinical efficacy characterization regardless of potential mechanism of action, we developed a gait testing platform for deep learning neural network analysis of drug impact on Glut1-deficient mouse locomotion.

A concise study of acetazolamide in glucose transporter type 1 deficiency (G1D) epilepsy.

Epilepsy constitutes the most common paroxysmal manifestation of glucose transporter type 1 deficiency (G1D) and is generally considered medication-refractory. It can also prove therapeutic diet-resistant. We examined acetazolamide effects in G1D motivated by several longstanding and recent observations: First, the electrographic spike-waves characteristic of absence seizures often resemble those of G1D and, since the 1950s, they have occasionally been treated successfully with acetazolamide, well before G1D was segregated from absence epilepsy as a distinct syndrome. Second, synaptic inhibitory neuron failure characterizes G1D and, in other experimental models, this can be ameliorated by drugs that modify cellular chloride gradient such as acetazolamide. Third, acetazolamide potently stimulates model cell glucose transport in vitro. Seventeen antiepileptic drug or therapeutic diet-refractory individuals with G1D treated with acetazolamide were thus identified via medical record review complemented by worldwide individual survey. Acetazolamide was tolerated and decreased seizures in 76% of them, with 58% of all persons studied experiencing seizure reductions by more than one-half, including those who first manifested myoclonic-astatic epilepsy or infantile spams. Eighty-eight percent of individuals with G1D continued taking acetazolamide for over 6 months, indicating sustained tolerability and efficacy. The results provide a novel avenue for the treatment and mechanistic investigation of G1D.

Greater sleep variability is associated with higher systemic inflammation in type 2 diabetes.

Sleep irregularity and variability have been shown to be detrimental to cardiometabolic health. The present pilot study explored if higher day-to-day sleep irregularity and variability were associated with systemic inflammation, as assessed by high-sensitivity C-reactive protein, in type 2 diabetes. Thirty-five patients with type 2 diabetes (mean age 54.3 years, 54.3% female) who were not shift-workers participated. The presence of diabetic retinopathy was determined. The standard deviation of sleep duration and sleep midpoint across all recorded nights were used to quantify sleep variability and regularity, respectively, assessed by 14-day actigraphy. The presence and severity of sleep apnea were assessed using an overnight home monitor. Low-density lipoprotein, haemoglobin A1C and high-sensitivity C-reactive protein were collected. Multiple regression analysis using natural-log-transformed values was performed to establish an independent association between sleep variability and high-sensitivity C-reactive protein. Twenty-two (62.9%) patients had diabetic retinopathy. The median (interquartile range) of high-sensitivity C-reactive protein was 2.4 (1.4, 4.6) mg L-1 . Higher sleep variability was significantly associated with higher high-sensitivity C-reactive protein (r = 0.342, p = 0.044), as was haemoglobin A1C (r = 0.431, p = 0.010) and low-density lipoprotein (r = 0.379, p = 0.025), but not sleep regularity, sleep apnea severity or diabetic retinopathy. Multiple regression analysis showed that higher sleep variability (B = 0.907, p = 0.038) and higher HbA1c (B = 1.519, p = 0.035), but not low-density lipoprotein, contributed to higher high-sensitivity C-reactive protein. In conclusion, higher sleep variability in patients with type 2 diabetes who were not shift-workers was independently associated with higher systemic inflammation, conferring increased cardiovascular risk. Whether sleep interventions to reduce sleep variability can reduce systemic inflammation and improve cardiometabolic health should be investigated.

Recommendations for Optimal Endoscopic Localization of Colorectal Neoplasms: A Delphi Consensus of National Experts.

BACKGROUND: Colonoscopy is the standard of care for diagnosis and evaluation of colorectal cancers before surgery. However, varied practices and heterogenous documentation affects communication between endoscopists and operating surgeons, hampering surgical planning. OBJECTIVE: This study aimed to develop recommendations for the use of standardized localization and reporting practices for colorectal lesions identified during lower GI endoscopy. DESIGN: A systematic review of existing endoscopy guidelines and thorough narrative review of the overall endoscopy literature were performed to identify existing practices recommended globally. SETTING: An online Delphi process was used to establish consensus recommendations based on a literature review. PATIENTS: Colorectal surgeons and gastroenterologists from across Canada who had previously demonstrated leadership in endoscopy, managed large endoscopy programs, produced high-impact publications in the field of endoscopy, or participated in the development of endoscopy guidelines were selected to participate. PRIMARY OUTCOME MEASURES: The primary outcomes measured were colorectal lesion localization and documentation practice recommendations important to planning surgical or advanced endoscopic excisions. RESULTS: A total of 129 of 197 statements achieved consensus after 3 rounds of voting by 23 experts from across Canada. There was more than 90% participation in each round. Recommendations varied according to lesion location in the cecum, colon, or rectum and whether the referral was planned for surgical or advanced endoscopic resection. Recommendations were provided for appropriate documentation, indications, location, and method of tattoo placement, in addition to photograph and real-time 3-dimensional scope configuration device use. LIMITATIONS: Because of a paucity of evidence, recommendations are based primarily on expert opinion. There may be bias, as all representatives were based in Canada. CONCLUSIONS: Best practices to optimize endoscopic lesion localization and communication are not addressed in previous guidelines. This consensus involving national experts in colorectal surgery and gastroenterology provides a framework for efficient and effective colorectal lesion localization. See Video Abstract at http://links.lww.com/DCR/C71 . RECOMENDACIONES PARA LA LOCALIZACIN ENDOSCPICA PTIMA DE LAS NEOPLASIAS COLORRECTALES UN CONSENSO DELPHI DE EXPERTOS NACIONALES: ANTECEDENTES:La colonoscopia es el estándar de atención para el diagnóstico y la evaluación de los cánceres colorrectales antes de la cirugía. Sin embargo, las prácticas variadas y la documentación heterogénea afectan la comunicación entre los endoscopistas y los cirujanos operadores, lo que dificulta la planificación quirúrgica.OBJETIVO:Este estudio tuvo como objetivo desarrollar recomendaciones para el uso de prácticas estandarizadas de localización y notificación de lesiones colorrectales identificadas en la endoscopia gastrointestinal inferior.DISEÑO:Se realizó una revisión sistemática de las pautas de endoscopia existentes y una revisión narrativa exhaustiva de la literatura general sobre endoscopia para identificar las prácticas existentes recomendadas a nivel mundial. Se utilizó un proceso Delphi en línea para establecer recomendaciones de consenso basadas en la revisión de la literatura.PARTICIPANTES:Se seleccionaron para participar cirujanos colorrectales y gastroenterólogos de todo Canadá que previamente habían demostrado liderazgo en endoscopia, manejado grandes programas de endoscopia, producido publicaciones de alto impacto en el campo de la endoscopia o que habían participado en el desarrollo de pautas de endoscopia.RESULTADOS:Localización de lesiones colorrectales y recomendaciones prácticas de documentación importantes para planificar escisiones quirúrgicas o endoscópicas avanzadas.RESULTADOS:129 de 197 declaraciones lograron consenso después de tres rondas de votación de 23 expertos de todo Canadá. Hubo >90% de participación en cada ronda. Las recomendaciones variaron según la ubicación de la lesión en el ciego, colon o recto, y si se planificó la derivación para resección quirúrgica o endoscópica avanzada. Se proporcionaron recomendaciones para la documentación adecuada, las indicaciones, la ubicación y el método de colocación del tatuaje, además de la fotografía y el uso del dispositivo de configuración del alcance 3D en tiempo real.LIMITACIONES:Debido a la escasez de evidencia, las recomendaciones se basan principalmente en la opinión de expertos. Puede haber sesgo, ya que los representantes tenían su sede en Canadá.CONCLUSIONES:Las mejores prácticas para optimizar la localización y comunicación de lesiones endoscópicas no se abordan en las guías anteriores. Este consenso que involucra a expertos nacionales en cirugía colorrectal y gastroenterología proporciona un marco para la localización eficiente y efectiva de lesiones colorrectales. Consulte Video Resumen en http://links.lww.com/DCR/C71 . (Traducción-Dr. Mauricio Santamaria ).

Variability in Communication and Reporting Practices Between Gastroenterologists and General Surgeons Contributes to Repeat Preoperative Endoscopy for Colorectal Neoplasms: A Qualitative Analysis.

BACKGROUND: Surgeons commonly repeat preoperative endoscopy before planned colorectal resections. The reasons for this are not entirely clear, and repeat endoscopy may lead to delays in curative resection, increased costs, and patient discomfort. OBJECTIVE: This study aimed to determine practice patterns, localization techniques, and processes of communication undertaken by endoscopy specialists in a high-volume regional health authority. DESIGN: This was a qualitative study involving standardized, semi-structured, in-depth interviews that were conducted in person. Data were analyzed using a thematic analysis approach. SETTINGS: The study was conducted at Canadian tertiary and community facilities. PARTICIPANTS: Ten general surgeons and 10 gastroenterologists were included using a convenience sampling technique. MAIN OUTCOME MEASURES: Interview questions were developed to understand the perspectives and practice patterns of endoscopists when approaching patients diagnosed with colorectal lesions requiring surgical resection. The decision-making process to perform a repeat preoperative endoscopy was assessed. RESULTS: Three key themes emerged: 1) patterns of communication, 2) feedback, and 3) trust. Thematic analysis revealed that poor communication and ambiguous documentation increased the likelihood of performing repeat preoperative endoscopy. Inconsistencies in tattooing practices and lesion location were important factors. Negative experiences and factors related to interprofessional trust emerged as key contributors to repeat preoperative endoscopy. LIMITATIONS: The transferability of findings to health care systems outside Canada may be limited and requires further study. CONCLUSIONS: Suboptimal endoscopic reporting contributes to gaps in communication among endoscopists. In addition, lack of consistent feedback and mutual trust may increase the likelihood of performing repeat preoperative lower endoscopy. Inconsistent tattooing practices pose significant concerns for accurate intraoperative lesion localization. Establishing collaborative work environments through joint educational initiatives may enhance communication and mitigate unnecessary repeat procedures. These results support the need for standardized guidelines and endoscopic reporting in the management of colorectal lesions. See Video Abstract at http://links.lww.com/DCR/B879 . LA VARIABILIDAD EN LAS PRCTICAS DE COMUNICACIN Y PRESENTACIN DE INFORMES ENTRE GASTROENTERLOGOS Y CIRUJANOS GENERALES CONTRIBUYE A REPETIR LA ENDOSCOPIA PREOPERATORIA PARA LAS NEOPLASIAS COLORRECTALES UN ANLISIS CUALITATIVO: ANTECEDENTES:Los cirujanos suelen repetir la endoscopia preoperatoria antes de las resecciones colorrectales planificadas. Las razones de esto no están del todo claras y la repetición de la endoscopia puede provocar retrasos en la resección curativa, aumento de los costos y malestar del paciente.OBJETIVO:Nuestro objetivo fue determinar patrones de práctica, técnicas de localización y procesos de comunicación realizados por especialistas en endoscopia, en una autoridad sanitaria regional, de alto volumen.DISEÑO:Este fue un estudio cualitativo, que involucró entrevistas estandarizadas, semiestructuradas y en profundidad que se llevaron a cabo en persona. Los datos se analizaron mediante un enfoque de análisis temático.ENTORNO CLINICO:El estudio se llevó a cabo en instalaciones comunitarias y terciarias canadienses.PARTICIPANTES:Se incluyeron 10 cirujanos generales y 10 gastroenterólogos, utilizando una técnica de muestreo por conveniencia.PRINCIPALES MEDIDAS DE VALORACION:Las preguntas de la entrevista se desarrollaron para comprender las perspectivas y los patrones de práctica de los endoscopistas, cuando se acercan a pacientes diagnosticados con lesiones colorrectales que requieren resección quirúrgica. Se evaluó el proceso de toma de decisiones para realizar una nueva endoscopia preoperatoria.RESULTADOS:Surgieron tres temas clave: 1) patrones de comunicación, 2) retroalimentación y 3) confianza. El análisis temático reveló que la pobre comunicación y la ambigua documentación aumentaron la probabilidad de realizar una nueva endoscopia preoperatoria. Las inconsistencias en las prácticas de tatuaje y la ubicación de las lesiones fueron factores importantes. Las experiencias pasadas negativas y los factores relacionados con la confianza interprofesional surgieron como contribuyentes clave para repetir la endoscopia preoperatoria.LIMITACIONES:La transferibilidad de los hallazgos a los sistemas de atención médica fuera de Canadá, puede ser limitada y requiere más estudios.CONCLUSIONES:Los informes endoscópicos subóptimos contribuyen a las brechas en la comunicación entre los endoscopistas. Además, la falta de retroalimentación consistente y la confianza mutua pueden aumentar la probabilidad de realizar una nueva endoscopia baja preoperatoria. Las prácticas inconsistentes de tatuaje, plantean preocupaciones importantes para la localización precisa de las lesiones intraoperatorias. El establecimiento de entornos de trabajo colaborativo a través de iniciativas educativas conjuntas pueden mejorar la comunicación y mitigar la repetición de procedimientos innecesarios. Estos resultados apoyan la necesidad de pautas estandarizadas e informes endoscópicos en el tratamiento de las lesiones colorrectales. Consulte Video Resumen en http://links.lww.com/DCR/B879 . (Traducción-Dr. Fidel Ruiz Healy ).

Inherited ichthyosis as a paradigm of rare skin disorders: Genomic medicine, pathogenesis, and management.

Great advances have been made in the field of heritable skin disorders using next-generation sequencing (NGS) technologies (ie, whole-genome sequencing, whole-exome sequencing, whole-transcriptome sequencing, and disease-targeted multigene panels). When NGS first became available, the cost and lack of access to these technologies were limiting factors; however, with decreasing sequencing costs and the expanding knowledge base of genetic skin diseases, fundamental awareness of NGS has become prudent. The heritable ichthyoses comprise a genotypically and phenotypically heterogeneous group of monogenic keratinization disorders characterized by persistent scaling, with at least 55 distinct genes currently implicated in causing nonsyndromic and syndromic forms of the disease. By providing a simplified overview of available NGS techniques and applying them in the context of ichthyosis, one of the most common genodermatoses, we hope to encourage dermatologists to offer, when appropriate, genetic testing earlier in patients with unsolved presentations. With the aid of NGS, dermatologists can provide diagnostic certainty in cases of suspected genodermatoses and offer potentially life-changing genome-guided and targeted therapies as they become available.

Healthcare delivery gaps in pain management within the first 3 months after discharge from inpatient noncardiac surgeries: a scoping review.

BACKGROUND: Poor pain control during the postoperative period has negative implications for recovery, and is a critical risk factor for development of persistent postsurgical pain. The aim of this scoping review is to identify gaps in healthcare delivery that patients undergoing inpatient noncardiac surgeries experience in pain management while recovering at home. METHODS: Searches were conducted by a medical librarian in PubMed, MEDLINE, EMBASE, EBSCO CINAHL, Web of Science, and Cochrane Database of Systematic Reviews for articles published between 2016 and 2022. Inclusion criteria were adults (≥18 yr), English language, inpatient noncardiac surgery, and included at least one gap in care for acute and/or persistent pain management after surgery within the first 3 months of recovery at home. Two reviewers independently screened articles for inclusion and extracted data. Quotations from each article related to gaps in care were synthesised using thematic analysis. RESULTS: There were 4794 results from databases and grey literature, of which 38 articles met inclusion criteria. From these, 23 gaps were extracted, encompassing all six domains of healthcare delivery (capacity, organisational structure, finances, patients, care processes and infrastructure, and culture). Identified gaps were synthesised into five overarching themes: education (22 studies), provision of continuity of care (21 studies), individualised management (10 studies), support for specific populations (11 studies), and research and knowledge translation (10 studies). CONCLUSIONS: This scoping review identified health delivery gaps during a critical period in postoperative pain management. These gaps represent potential targets for quality improvement and future research to improve perioperative care and longer-term patient-centred outcomes. SCOPING REVIEW PROTOCOL: Open Science Framework (https://osf.io/cq5m6/).

Challenges in Inter-rater Agreement on Lamina Propria Fibrosis in Esophageal Biopsies.

BACKGROUND: Mucosal biopsies in eosinophilic esophagitis (EoE) can exhibit lamina propria (LP) fibrosis, which may portend stenotic complications; however, the histologic diagnosis of LP fibrosis is subjective. We sought to assess and improve the consistency of LP fibrosis diagnosis among our pathologist group. METHODS: At a large pediatric hospital, 25 esophageal biopsy slides from 19 patients (16 with EoE) exhibiting a wide spectrum of LP area, artifacts, and fibrosis severity were scanned into whole-slide images. Staff pediatric pathologists (n = 8) separate from the authors classified each biopsy by LP adequacy and fibrosis severity 1 month before and after completion of an educational tutorial. Consensus was defined as >70% agreement. RESULTS: At baseline, 16/25 (64%) cases reached consensus for no fibrosis (n = 3), fibrosis (n = 7), or inadequate LP (n = 6); agreement was fair (α = 0.34). Post-tutorial, 13/25 (52%) cases reached consensus for no fibrosis (n = 2), fibrosis (n = 7), or inadequate LP (n = 4); agreement was again fair (α = 0.33). There was moderate agreement in grading of fibrosis severity (α = 0.54). CONCLUSION: We document only fair-to-moderate agreement in the diagnosis of esophageal LP fibrosis and adequacy in a large pediatric pathologist group despite targeted education, highlighting a challenge in incorporating this feature into EoE research and clinical decision-making.

Patient and surgeon preferences for early ileostomy closure following restorative proctectomy for rectal cancer: why aren't we doing it?

BACKGROUND: Early ileostomy closure (EIC), ≤ 2 weeks from creation, is a relatively new practice. Multiple studies have demonstrated that this approach is safe, feasible, and cost-effective. Despite the demonstrated benefits, this is neither routine practice, nor has it been studied, in North America. This study aimed to assess patient and surgeon perspectives about EIC. METHODS: A mixed-methods, cross-sectional study of patients and surgeons was performed. Rectal cancer survivors from a single institution who underwent restorative proctectomy with diverting loop ileostomy and subsequent closure within the last 5 years were contacted. North American surgeons with high rectal cancer volumes (> 20 cases/year) were included. Surveys (patients) and semi-structured interviews (surgeons) were conducted. Analysis employed descriptive statistics and thematic analysis, respectively. RESULTS: Forty-eight patients were surveyed (mean age 65.1 ± 11.8 years; 54.2% male). Stoma closure occurred after a median of 7.7 months (IQR 4.8-10.9) and 50.0% (24) found it "difficult" or "very difficult" to live with their stoma. Patients considered improvement in quality of life and quicker return to normal function the most important advantages of EIC, whereas the idea of two operations in two weeks being too taxing on the body was deemed the biggest disadvantage. Most patients (35, 72.9%) would have opted for EIC. Surgeon interviews (15) revealed 4 overarching themes: (1) there are many benefits to EIC; (2) specific patient characteristics would make EIC an appropriate option; (3) many barriers to implementing EIC exist; and (4) many logistical hurdles need to be addressed for successful implementation. Most surgeons (12, 80.0%) would "definitely want to participate" in a North American randomized-controlled trial (RCT) on EIC for rectal cancer patients. CONCLUSIONS: Implementing EIC poses many logistical challenges. Both patients and surgeons are interested in further exploring EIC and believe it warrants a North American RCT to motivate a change in practice.

Rod photoreceptor activation and deactivation in early-stage diabetic eye disease.

PURPOSE: To infer rod phototransduction activation and deactivation characteristics in diabetics who have mild or no clinically-apparent retinopathy. METHODS: Fifteen non-diabetic controls, 15 diabetics with no clinically-apparent diabetic retinopathy (NDR), and 15 diabetics with mild non-proliferative diabetic retinopathy (MDR) participated. Dark-adapted flash electroretinograms (3.2 to 4.4 log scot td-s) were recorded to assess rod activation. The a-waves were fit with a Gaussian model to derive Rmp3 (maximum photoreceptor response amplitude) and S (phototransduction sensitivity). Rod deactivation was assessed with a paired flash paradigm, in which a-waves were measured for two flashes separated by inter-stimulus intervals (ISIs) of 0.125 to 16 s. The ISI needed for the a-wave amplitude of the second flash to recover to 50% of the first flash (t50) was determined. The effect of stimulus retinal illuminance on activation and deactivation was evaluated in a subset of control subjects. RESULTS: Analysis of variance indicated that both diabetic groups had significant log S reductions compared to controls (p < 0.001). Mean S was reduced by approximately 49% and 78% for the NDR and MDR groups, respectively. In contrast, log Rmp3 and log t50 did not differ significantly among the groups (both p > 0.08). Reducing stimulus retinal illuminance significantly reduced S, but did not significantly affect Rmax or t50. CONCLUSIONS: Only phototransduction sensitivity was abnormal in this sample of diabetic subjects. The normal deactivation kinetics suggests that circulating rod current is normal. These findings begin to constrain possible explanations for abnormal rod function in early diabetic retinal disease.

Occult retinopathy following treatment of Hepatitis C with glecaprevir/pibrentasvir (Mavyret).

BACKGROUND/PURPOSE: Medication-induced ocular toxicity is an important consideration in the differential diagnosis of unexplained visual disturbance. We present a case of visual disturbance after starting treatment with glecaprevir/pibrentasvir (Mavyret), a therapy for Hepatitis C virus approved by the FDA in 2017. METHODS: A 50-year-old male with no significant ocular history experienced bilateral visual disturbance, including visual field and acuity loss, shortly after initiating treatment with Mavyret for Hepatitis C. Examination of the anterior and posterior segments was unremarkable, and no abnormalities could be identified on multimodal imaging of the eye and brain, including MRI, SD-OCT, and fundus autofluorescence. Extensive testing for inflammatory, infectious, nutritional, and genetic etiologies for optic neuropathy and retinopathy was negative. RESULTS: Electrophysiology testing was pursued to narrow the broad differential diagnosis. Full-field electroretinography and multi-focal electroretinography detected deficiencies in the rod and cone visual pathways and attenuated electrophysiologic responses in the fovea. Pattern electroretinography and visually-evoked potentials demonstrated macula dysfunction. Taken together, electrophysiologic data suggested diffuse retinal dysfunction, which was most pronounced in the macula. CONCLUSIONS: Given the temporal relationship between Mavyret administration and vision loss in our patient, and the absence of an underlying cause after extensive evaluation, we propose that Mavyret may be associated with a toxic occult retinopathy characterized by panretinal dysfunction without clinically apparent structural findings.

Acquired ichthyosis, asteatotic dermatitis or xerosis? An update on pathoetiology and drug-induced associations.

Acquired ichthyosis (AI) is a relatively rare cutaneous entity characterized by transient, generalized scaling and pruritus in the absence of family history of ichthyosis or atopic disease. The hyperkeratosis in AI can range from the mild, white-to-brown scaling resembling that in ichthyosis vulgaris (IV) to the more prominent dark brown scaling phenotype, similar to that found in lamellar ichthyosis. The disease can wax and wane in relation to endogenous and/or exogenous factors. Histopathology of AI is similar to that found in IV. AI is usually of cosmetic concern to patients but can, in some cases, reflect the presence of more serious conditions, including malignancies, autoimmune diseases or metabolic disorders. In some cases, AI can be an adverse effect of a medication or the cutaneous symptom of a toxic exposure. Other conditions, such as severe xerosis or eczema, can present with clinical findings similar to AI, making diagnosis a challenge. Furthermore, cases of AI are sporadic throughout the literature and have been documented across a wide variety of medical settings distinct from dermatology, which often contribute to misdiagnosis of this disease. Definitive management requires prompt identification and treatment of the inciting factors combined with conservative therapies, which can include topical emollients, keratolytics, retinoids or corticosteroids, and in rare cases, oral retinoids.

Hemoglobin ß-Globin Variants In Hispanic Patients: An Institutional Experience From Dallas, Texas.

Hemoglobinopathies are the most common single-gene disorders in humans. There are 1,424 variants of human hemoglobin described with 951 involving the ß-globin gene. Ancestry and geography play a significant role in the incidence and nature of hemoglobinopathies, with African, Asian, and Mediterranean populations and their descendants being amongst the most affected. Investigation of variants in individuals of Hispanic descent is needed to reflect the changing demographics of the United States. Hemoglobin ß-globin evaluation through gel electrophoresis, high-performance liquid chromatography, and HBB gene sequencing was performed on patients from Texas hospitals between 2010 and 2015 and demographic parameters (age, sex, ethnicity) was subsequently analyzed. A total of 846 patients underwent hemoglobinopathy evaluation. A ß chain variant was detected in 628 of the 846 total patients. Hispanic patients represented 37% (314/846 patients), which were equally distributed between females (50%; 156/314) and males (50%; 156/314). A ß-globin chain variant was found in 67% of Hispanic patients with a distribution across 10 variants seen in greater than 1% of patients. For hemoglobin variants, an understanding of the regional and ethnic prevalence will improve patient care through more effective screening and identification of the variant, early diagnosis, and appropriate treatment if necessary, and better genetic counseling.

Colorectal polyp classification and management of complex polyps for surgeon endoscopists.

Increasing familiarity with advanced endoscopic excision techniques allows for more colorectal lesions to be removed without major surgery. Endoscopic excision with negative margins is adequate for most polyps and low-risk T1 cancers. The use of modern polyp classification techniques based on size, morphology and pit pattern by an experienced endoscopist allow for an optical diagnosis of these lesions and can predict, with high accuracy, which lesions contain malignant disease and the level of invasion. A surgeon endoscopist must be able to recognize which complex polyps can be resected with advanced polypectomy techniques and which require upfront surgery. We aimed to provide an overview of polyp classification techniques to help surgeons select the correct treatment algorithm for advanced colorectal lesions based on their visual characteristics at index endoscopy.

Total neoadjuvant therapy for rectal cancer: a guide for surgeons.

The modern management of rectal cancers continues to evolve. With the release of data from new landmark randomized controlled trials (RAPIDO, PRODIGE-23), total neoadjuvant therapy (TNT) has moved to the forefront of locally advanced rectal cancer treatment and is considered a standard option in selected patients. Total neoadjuvant therapy promises enhanced systemic disease control, better treatment adherence and less time with an ostomy. However, TNT as currently described encompasses a number of different potential treatment options that differ significantly in terms of their radiation dosage, chemotherapy regimen and order of treatments administered. Being familiar with TNT regimens will be important for rectal cancer surgeons to appropriately advocate for their patients and optimize their outcomes. This article serves as a primer for the general surgeon and offers a pragmatic overview of the indications, realistic expected benefits and potential downsides of each TNT regimen.

The Slow Progression of Diabetic Retinopathy Is Associated with Transient Protection of Retinal Vessels from Death.

The purpose of this study was to investigate the reason that diabetic retinopathy (DR) is delayed from the onset of diabetes (DM) in diabetic mice. To this end, we tested the hypothesis that the deleterious effects of DM are initially tolerated because endogenous antioxidative defense is elevated and thereby confers resistance to oxidative stress-induced death. We found that this was indeed the case in both type 1 DM (T1D) and type 2 DM (T2D) mouse models. The retinal expression of antioxidant defense genes was increased soon after the onset of DM. In addition, ischemia/oxidative stress caused less death in the retinal vasculature of DM versus non-DM mice. Further investigation with T1D mice revealed that protection was transient; it waned as the duration of DM was prolonged. Finally, a loss of protection was associated with the manifestation of both neural and vascular abnormalities that are diagnostic of DR in mice. These observations demonstrate that DM can transiently activate protection from oxidative stress, which is a plausible explanation for the delay in the development of DR from the onset of DM.