Polypathology-associated neurodegeneration after remote head injury.

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality worldwide. TBI ranges from mild to severe and is a recognized risk factor for later neurodegenerative conditions including chronic traumatic encephalopathy (CTE), Alzheimer disease (AD) and Parkinson disease (PD). The development of CTE is typically associated with repetitive exposure to mild TBI (mTBI), while a single moderate-to-severe TBI is considered a risk factor for AD and PD. Polypathology is common, and the lines between these conditions post TBI can be somewhat blurred. The mechanisms through which TBI leads to future neurodegeneration are not well understood. Heterogeneity and distance from the injury or injuries and individual genetic and environmental factors make clinical studies difficult. We present the case of an 82-year-old man who died 4 years after developing a phenotypically mixed dementia with neuropsychiatric features and parkinsonism. He had a remote history of a severe TBI 40 years prior, following a road traffic accident which caused a large right frontal injury, requiring neurosurgical intervention. Post-mortem neuropathological examination demonstrated abnormal phosphorylated-Tau (p-Tau), beta-amyloid plaques (Aß) and α-synuclein deposition. Spatial immunohistochemical analysis demonstrated increased perivascular accumulation of p-Tau with blood-brain barrier (BBB) disruption at the site of injury, which decreased with distance from the injury site. The appearances are suggestive of initial vascular disruption with persisting BBB disruption as a driver of the pathology.

Matrix metalloproteinase-3 (MMP-3)-mediated gene therapy for glaucoma.

Approximately 80 million people globally are affected by glaucoma, with a projected increase to over 110 million by 2040. Substantial issues surrounding patient compliance remain with topical eye drops, and up to 10% of patients become treatment resistant, putting them at risk of permanent vision loss. The major risk factor for glaucoma is elevated intraocular pressure, which is regulated by the balance between the secretion of aqueous humor and the resistance to its flow across the conventional outflow pathway. Here, we show that adeno-associated virus 9 (AAV9)-mediated expression of matrix metalloproteinase-3 (MMP-3) can increase outflow in two murine models of glaucoma and in nonhuman primates. We show that long-term AAV9 transduction of the corneal endothelium in the nonhuman primate is safe and well tolerated. Last, MMP-3 increases outflow in donor human eyes. Collectively, our data suggest that glaucoma can be readily treated with gene therapy-based methods, paving the way for deployment in clinical trials.

Prospective randomized comparison of three-dimensional (3D) versus conventional laparoscopy in total colectomy for ulcerative colitis.

BACKGROUND: 3D laparoscopy has been proposed with the aim of improving the depth perception and overall operative performance. To aim of this study is to compare 3D laparoscopy with conventional 2D laparoscopy in terms of operative time and visual parameters. METHODS: This is a prospective, randomized, single-center trial designed to determine 10% reduction in the mean operative time. Ulcerative colitis patients >18 years of age who underwent laparoscopic total abdominal colectomy with end ileostomy between 2015 and 2020 were included. Patients were randomized into 3D and 2D laparoscopy groups. Duration of operation and surgeons' evaluation of the visualization system were the primary outcomes. RESULTS: Fifty-three subjects (26 in 2D, 27 in 3D group) were included in the analysis, with 56% being male. Mean age and body mass index were 40 (16.3) years and 23.5 (4.7) kg/m2 , respectively. Twenty-five subjects underwent single port laparoscopic surgery, of whom 13 were in 3D and 12 in 2D group. Mean operative time was 75.3 (30.8) versus 82.7 (38.6) minutes (P = 0.4) for 3D and 2D groups, respectively. Operative times spent for individual steps were comparable. Post-operative minor complications (8 in 3D versus 8 in 2D, P = 1) and median number of times for scope maintenance were also similar between the groups. 69% of the visual evaluation survey results favoured 3D over 2D (P = 0.014). CONCLUSION: Three-dimensional laparoscopy for total colectomy in ulcerative colitis patients is safe and feasible option providing better visualization with no difference in operative time.

Do surface morphology and pit pattern have a role in predicting cancer for colon polyps in North America?

BACKGROUND: The surface morphology of colorectal polyps is well correlated with submucosal invasion in Eastern Countries but not in North America. We aimed to investigate associations between the Paris classification, surface morphology, and Kudo pit pattern to submucosal invasion in advanced endoscopic resection techniques. METHODS: We retrospectively analyzed prospectively collected data of consecutive advanced endoscopic procedures conducted by a single surgeon between August 2017 and October 2018. The data included patients' demographics, the endoscopic finding of polyps (Paris, Kudo, and surface morphology), and pathology results. RESULTS: The study consisted of 138 lesions, and the mean age was 67 ± 10 years. The most common polyp locations were cecum (n = 41, 30%) followed by ascending colon (n = 28, 20%), and sigmoid colon (n = 18, 13%).The median polyp size was 30 mm (25-40). The en-bloc resection rate was 96%, and 11 (8%) polyps had adenocarcinoma with submucosal invasion. Nine patients (6.5%) had late bleeding, and 3 (2.2%) perforation occurred. Polyps with pit pattern of Kudo IV (n = 4, 36.4%) and Kudo V (n = 6, 54.5%) were associated with submucosal invasion. CONCLUSIONS: Surface morphology and pit pattern can predict submucosal invasion in the North American patient population. Polyp morphology may aid polyp selection for advanced endoscopic interventions.

Does milk of magnesia impact length of hospital stay after major colorectal resection.

BACKGROUNDS: Milk of magnesia (MoM) has been reported to accelerate return of bowel function following surgery. However, there is insufficient evidence regarding the impact of MoM on postoperative recovery after colorectal surgery. We aimed to determine the impact of MoM on postoperative length of stay in patients undergoing colorectal surgery. METHODS: All patients who underwent colorectal resection without an ileostomy between 2015 and 2018 were included. Patients were divided into two groups based on whether postoperative MoM (MoM) was administered or not, according to surgeons' prescribing preferences. Consecutive patients of surgeons who prescribe MoM were included in the MoM group, while consecutive patients of surgeons who prefer not to prescribe MoM served as the control group. Age, gender, preoperative comorbidities, surgical approach, length of stay, readmission, postoperative complications and mortality were evaluated and compared between the groups. RESULTS: A total of 3292 patients were included; 523 (15.9%) patients were prescribed MoM. Patients in the MoM group were found to be significantly older, with higher BMI and ASA class, and more often undergoing operations for cancer resection or colostomy creations, than the control group. Postoperative complications were comparable between the groups. On multivariable linear regression, MoM use was associated with a 14.1% reduction in length of stay (MoM group 4 (2; 8), control group 5 (3; 8 P = 0.006)). CONCLUSION: MoM as adjunct medication in the postoperative period following colorectal surgery is associated with reduced length of stay, without an increase in postoperative complications.

Venous Thromboembolism in Patients Admitted for IBD: An Enterprise-Wide Experience of 86,000 Hospital Encounters.

BACKGROUND: Recommendations regarding venous thromboembolism prophylaxis in patients admitted to the hospital for IBD continue to evolve. OBJECTIVE: This study aimed to determine the 90-day rate and risk factors of deep venous thromboembolism and pulmonary embolism in cohorts of patients with IBD admitted to medical and surgical services. DESIGN: This was a retrospective review. SETTING: The study was conducted at a quaternary IBD referral center. PATIENTS: The study included adult patients ( > 18 y of age) with a known diagnosis of either ulcerative colitis or Crohn's disease who had an inpatient hospital admission for IBD between January 1, 2002, and January 1, 2020. MAIN OUTCOME MEASURES: The primary outcome measures were 90-day rate of deep venous thromboembolism and pulmonary embolism among admitted patients. RESULTS: A total of 86,276 hospital admissions from 16,551 patients with IBD occurred between January 1, 2002, and January 1, 2020. A total of 35,992 patients (41.7%) were given subcutaneous heparin for venous thromboembolism prophylaxis, and 8188 patients (9.49%) were given enoxaparin for venous thromboembolism prophylaxis during the inpatient hospital admission. From the date of hospital admission, the 90-day rate of deep venous thromboembolism was 4.3% (n = 3664); of these, 1731 patients (47%) were diagnosed during the admission and 1933 patients (53%) were diagnosed after discharge. From the date of hospital admission, the 90-day rate of pulmonary embolism was 2.4% (n = 2040); of these, 960 patients (47%) were diagnosed during admission and 1080 patients (53%) were diagnosed after discharge. LIMITATIONS: The study was limited by its retrospective nature and unmeasured severity of the disease. CONCLUSIONS: Patients admitted for IBD had a 90-day deep venous thromboembolism event rate of 4.3% and pulmonary embolism event rate of 2.4%. More than half of the events occurred after discharge, and venous thromboembolism events were higher among patients with IBD admitted to a medical service than those admitted to a surgical service. See Video Abstract at http://links.lww.com/DCR/B947 . TROMBOEMBOLIA VENOSA EN PACIENTES INGRESADOS CON ENFERMEDAD INFLAMATORIA INTESTINAL UNA EXPERIENCIA EN TODA LA EMPRESA DE ENCUENTROS HOSPITALARIOS: ANTECEDENTES:Recomendaciones sobre la profilaxis de tromboembolia venosa en pacientes ingresados con enfermedad inflamatoria intestinal (EII) continúa evolucionando.OBJETIVO:Determinar la tasa a 90 días y los factores de riesgo de tromboembolia venosa profunda y embolia pulmonar en cohortes de pacientes ingresados con EII médico y quirúrgico.DISEÑO:Esta fue una revisión retrospectiva.AJUSTE:El estudio se llevó a cabo en un centro cuaternario de derivación de EII.PACIENTES:Se incluyeron pacientes adultos (> 18 años) con diagnóstico conocido de colitis ulcerosa o enfermedad de Crohn que fueron hospitalizados por EII entre el 1 de Enero de 2002 y el 1 de Enero de 2020.PRINCIPALES MEDIDAS DE RESULTADOS:Las medidas principales fueron la tasa de tromboembolia venosa profunda a 90 días y la embolia pulmonar entre los pacientes ingresados.RESULTADOS:Un total de 86.276 ingresos hospitalarios de 16.551 pacientes con EII ocurrieron entre el 1 de Enero de 2002 y el 1 de Enero de 2020. A un total de 35.992 (41,7%) se les administró heparina subcutánea para profilaxis de tromboembolia venosa y a 8.188 (9,49%) se les administró enoxaparina para profilaxis de tromboembolia venosa durante el ingreso hospitalario. A partir de la fecha de ingreso hospitalario, la tasa de tromboembolia venosa profunda a 90 días fue del 4,3% (n = 3.664); de estos 1.731 (47%) se diagnosticaron durante el ingreso y 1.933 (53%) se diagnosticaron después del alta. Desde la fecha de ingreso hospitalario, la tasa de embolia pulmonar a los 90 días fue de 2,4% (n = 2.040); De estos, 960 (47%) fueron diagnosticados durante el ingreso y 1.080 (53%) fueron diagnosticados después del alta.LIMITACIONES:El estudio fue retrospectivo y no se midió la gravedad de la enfermedad.CONCLUSIÓNES:Los pacientes ingresados por EII tuvieron una tasa de tromboembolia venosa profunda y de eventos de embolia pulmonar de 4,3% y 2,4%, respectivamente, a 90 días. Más de la mitad de los eventos ocurrieron después del alta y los eventos de TEV fueron más altos entre los pacientes de EII médicos que quirúrgicos. Consulte Video Resumen en http://links.lww.com/DCR/B947 . (Traducción- Dr. Yesenia Rojas-Khalil ).

Effect of Incisional Negative Pressure Wound Therapy on Surgical Site Infections in High-Risk Reoperative Colorectal Surgery: A Randomized Controlled Trial.

BACKGROUND: Colorectal resections have relatively high rates of surgical site infections causing significant morbidity. Incisional negative pressure wound therapy was introduced to improve wound healing of closed surgical incisions and to prevent surgical site infections. OBJECTIVE: This randomized controlled trial aimed to investigate the effect of incisional NPWT on superficial surgical site infections in high-risk, open, reoperative colorectal surgery. DESIGN: This was a single-center randomized controlled trial conducted between July 2015-October 2020. Patients were randomly assigned to incisional negative pressure wound therapy or standard gauze dressing with a 1:1 ratio. A total of 298 patients were included. SETTINGS: This study was conducted at the colorectal surgery department of a tertiary-level hospital. PATIENTS: This study included patients older than 18 years who underwent elective reoperative open colorectal resections. Patients were excluded who had open surgery within the past 3 months, who had active surgical site infection, and who underwent laparoscopic procedures. MAIN OUTCOME MEASURES: The primary outcome was superficial surgical site infection within 30 days. Secondary outcomes were deep and organ-space surgical site infections within 7 days and 30 days, postoperative complications, and length of hospital stay. RESULTS: A total of 149 patients were included in each arm. The mean age was 51 years, and 49.5% were women. Demographics, preoperative comorbidities, and preoperative albumin levels were comparable between the groups. Overall, most surgeries were performed for IBD, and 77% of the patients had an ostomy fashioned during the surgery. No significant difference was found between the groups in 30-day superficial surgical site infection rate (14.1% in control versus 9.4% in incisional negative pressure wound therapy; p = 0.28). Deep and organ-space surgical site infections rates at 7 and 30 days were also comparable between the groups. Postoperative length of stay and complication rates (Clavien-Dindo grade) were also comparable between the groups. LIMITATIONS: The patient population included in the trial consisted of a selected group of high-risk patients. CONCLUSIONS: Incisional negative pressure wound therapy was not associated with reduced superficial surgical site infection or overall complication rates in patients undergoing high-risk reoperative colorectal resections. See Video Abstract at http://links.lww.com/DCR/B956 . EFECTO DE LA TERAPIA DE HERIDA INSICIONAL CON PRESIN NEGATIVA EN INFECCIONES DEL SITIO QUIRRGICO EN CIRUGA COLORRECTAL REOPERATORIA DE ALTO RIESGO UN ENSAYO CONTROLADO ALEATORIZADO: ANTECEDENTES:Las resecciones colorrectales tienen tasas relativamente altas de infecciones del sitio quirúrgico que causan una morbilidad significativa. La terapia de heridas incisionales con presión negativa se introdujo para mejorar la cicatrización de las heridas de incisiones quirúrgicas cerradas y para prevenir infecciones del sitio quirúrgico.OBJETIVO:El objetivo de este ensayo controlado y aleatorizado fue investigar el efecto de la terapia de herida incisional con presión negativa en infecciones superficiales del sitio quirúrgico en cirugía colorrectal re operatoria, abierta y de alto riesgo.DISEÑO:Ensayo controlado y aleatorizado de un solo centro entre julio de 2015 y octubre de 2020. Los pacientes fueron aleatorizados para recibir tratamiento para heridas incisionales con presión negativa o vendaje de gasa estándar en una proporción de 1:1. Se incluyeron un total de 298 pacientes.AJUSTE:Este estudio se realizó en el departamento de cirugía colorrectal de un hospital de tercer nivel.PACIENTES:Se incluyeron pacientes mayores de 18 años que se fueron sometidos a resecciones colorrectales abiertas, re operatorias y electivas. Se excluyeron aquellos pacientes que tuvieron cirugía abierta en los últimos 3 meses, con infección activa del sitio quirúrgico y que fueron sometidos a procedimientos laparoscópicos.PRINCIPALES MEDIDAS DE RESULTADO:El resultado primario fue infección superficial del sitio quirúrgico dentro de los 30 días. Los resultados secundarios fueron infecciones del sitio quirúrgico profundas y del espacio orgánico dentro de los 7 y 30 días, las complicaciones posoperatorias y la duración de la estancia hospitalaria.RESULTADOS:Se incluyeron un total de 149 pacientes en cada brazo. La edad media fue de 51 años y el 49,5% fueron mujeres. La demografía, las comorbilidades preoperatorias y los niveles de albúmina preoperatoria fueron comparables entre los grupos. En general, la mayoría de las cirugías fueron realizadas por enfermedad inflamatoria intestinal y al 77 % de los pacientes se les confecciono una ostomía durante la cirugía. No hubo diferencias significativas entre los grupos en la tasa de infección del sitio quirúrgico superficial a los 30 días (14,1 % en el control frente a 9,4 % en el tratamiento de herida incisional con presión negativa, p = 0,28). Las tasas de infecciones del sitio quirúrgico profundas y del espacio orgánico a los 7 y 30 días también fueron comparables entre los grupos. La duración de la estancia postoperatoria y las tasas de complicaciones (Clavien-Dindo Graduacion) también fueron comparables entre los grupos.LIMITACIONES:La población de pacientes incluida en el ensayo consistió en un grupo seleccionado de pacientes de alto riesgo.CONCLUSIONES:Video Resumen en http://links.lww.com/DCR/B956 . (Traducción-Dr. Osvaldo Gauto ).

Implementation of a standardized surgical technique in robot-assisted restorative rectal cancer resection: a single center cohort study.

BACKGROUND: Despite increasing focus on the technical performance of total mesorectal excision over recent decades, anastomotic leakage (AL) continues to be a serious complication for many patients, even in the hands of experienced surgical teams. This study describes implementation of standardized surgical technique in an effort to reduce variability, decrease the risk of anastomotic leakage, and improve associated short-term outcomes for rectal cancer patients undergoing robot-assisted restorative rectal resection (RRR). METHODS: We evaluated all rectal cancer patients undergoing robot-assisted RRR at Aarhus University Hospital between 2017 and 2020. Six standardized surgical steps directed to improve anastomotic healing were mandatory for all RRR. Additional changes were made during the period with prohibition of systemic dexamethasone and limiting the use of endoscopic stapling devices. RESULTS: The use of the full standardization, including all six surgical steps, increased from 40.3% (95% CI, 0.28-0.54) to 86.2% (95% CI, 0.68-0.95). The incidence of AL decreased from 21.0% (95% CI, 0.12-0.33) to 6.9% (95% CI, 0.01-0.23). Length of hospital stay (LOS) decreased from 6 days (range 2-50) to 5 days (range 2-26). The rate of patients readmitted within 90 days decreased from 21.0% (95% CI, 0.12-0.33), to 6.9% (95% CI, 0.01-0.23). CONCLUSION: The full standardization was effectively implemented for rectal cancer patients undergoing robot-assisted RRR. The risk of AL, LOS and readmission decreased during the study period. A team focus on high-reliability and peri-operative complications can improve patient outcomes.

Restorative proctocolectomy with ileal pouch-anal anastomosis in elderly patients - is advanced age a contraindication?

AIM: We aimed to determine pouch function and retention rate for restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC) in elderly patients. METHODS: We identified patients over 50 years old subjected to IPAA for confirmed pathological UC from 1980 until 2016. Patients were grouped according to age: 50-59, 60-69 and 70+ years. Short and long-term outcomes and quality of life (QOL) were compared among the groups. RESULTS: Six hundred and one patients were identified (399 (66.4%) between 50-59 181 (30.1%) between 60-69, and 21 (3.5%) over 70 years of age). More males were in the 70+ arm, and more two-stage procedures were performed in this group. Wound infection increased with age (P = 0.023). There was a trend of more fistula and pouchitis in the 70+ patients (P = 0.052 and P = 0.055, respectively). Pouch failure rate increased with age, and it was statistically significant in the 70+ cohort (P = 0.015). Multivariate stepwise logistic regression showed that pelvic sepsis (HR 4.8 (95% CI 1.5-15.4), P = 0.009), fistula (HR 6.0 (95% CI 1.7-21.5), and mucosectomy with handsewn anastomosis (HR 4.5 (95% CI 1.4-14.7)), were independently associated with pouch failure. No difference was observed in the QOL among the groups, but pouch function was better for patients younger than 60 years. CONCLUSION: In elderly patients with UC, IPAA may be offered with reasonable functional outcomes, and ileal pouch retention rates, as an alternative to the permanent stoma. Stapled anastomosis increases the chance of pouch retention and should be recommended as long as the distal rectum does not carry dysplasia.

Microvascular stabilization via blood-brain barrier regulation prevents seizure activity.

Blood-brain barrier (BBB) dysfunction is associated with worse epilepsy outcomes however the underlying molecular mechanisms of BBB dysfunction remain to be elucidated. Tight junction proteins are important regulators of BBB integrity and in particular, the tight junction protein claudin-5 is the most enriched in brain endothelial cells and regulates size-selectivity at the BBB. Additionally, disruption of claudin-5 expression has been implicated in numerous disorders including schizophrenia, depression and traumatic brain injury, yet its role in epilepsy has not been fully deciphered. Here we report that claudin-5 protein levels are significantly diminished in surgically resected brain tissue from patients with treatment-resistant epilepsy. Concomitantly, dynamic contrast-enhanced MRI in these patients showed widespread BBB disruption. We show that targeted disruption of claudin-5 in the hippocampus or genetic heterozygosity of claudin-5 in mice exacerbates kainic acid-induced seizures and BBB disruption. Additionally, inducible knockdown of claudin-5 in mice leads to spontaneous recurrent seizures, severe neuroinflammation, and mortality. Finally, we identify that RepSox, a regulator of claudin-5 expression, can prevent seizure activity in experimental epilepsy. Altogether, we propose that BBB stabilizing drugs could represent a new generation of agents to prevent seizure activity in epilepsy patients.

A Comparison of Perineal Myocutaneous Flaps Following Abdominoperineal Excision of the Rectum for Anorectal Pathology.

BACKGROUND: Flap-based reconstruction following abdominoperineal resection has been used to address the resultant soft tissue defect and reduce postoperative wound complications. Vertical rectus abdominis myocutaneous flaps have been the traditional choice, but locoregional flaps have attracted attention in minimally invasive resection because they avoid additional abdominal dissection. However, few data exist comparing flap types. OBJECTIVE: To compare outcomes for different types of perineal reconstruction in patients undergoing abdominoperineal resection exclusively for anorectal pathology. DESIGN: This was a retrospective comparative study. SETTING: This study was conducted at a large, tertiary referral institution. PATIENTS: Following Institutional Review Board approval, prospectively maintained clinical and financial databases were interrogated and cross-referenced for patients undergoing proctectomy or abdominoperineal resection with flap reconstruction from 2007 to 2018. Patients with primary gynecological or urological pathology were excluded. MAIN OUTCOME MEASURES: The primary outcome was flap complication rate. Secondary outcomes included perineal hernia rate, donor site complications, emergency department consult after discharge, readmission <90 days, and length of stay. Data were analyzed using univariate and multivariate techniques. RESULTS: A total of 135 patients (79 female, median age 58 years) were included: 68 rectus, 52 gluteal, and 15 gracilis flap reconstructions. Median follow-up was 46 months. Rates of both major and minor flap complications were similar for rectus and gluteal flaps, even when controlling for differences between groups via multivariate analysis ( p > 0.9), including extent of resection and use of mesh. For all flaps, American Society of Anesthesiology score ≥3 was the only independent predictor of major, but not minor, flap complications. For rectus and gluteal flaps, smoking, female sex, and American Society of Anesthesiology score ≥3 were independent predictors of major flap complications ( p < 0.05). LIMITATIONS: This study was limited by its retrospective nature and potential selection bias associated with flap choice; it was also impossible to quantify defect size. CONCLUSION: Gluteal flaps have similar complication rates to rectus flaps and may be considered for patients who are otherwise suitable for minimally invasive abdominoperineal resection. See Video Abstract at http://links.lww.com/DCR/B866 .Una comparación de los colgajos miocutáneos perineales después de la escisión abdominoperineal del recto para patología anorectal. ANTECEDENTES: La reconstrucción con colgajo después de la resección abdominoperineal se ha utilizado para abordar el defecto de tejido blando resultante y reducir las complicaciones postoperatorias de la herida. Los colgajos miocutáneos verticales del recto abdominal han sido la elección tradicional, pero los colgajos locorregionales han atraído la atención en la resección mínimamente invasiva porque evitan la disección abdominal adicional. Sin embargo, existen pocos datos que comparen los tipos de colgajos.

Minocycline suppresses disease-associated microglia (DAM) in a model of photoreceptor cell degeneration.

As the resident immune cells in the retina, microglia play important homeostatic roles in retinal immune regulation and neuroprotection. However, chronic microglia activation is a common hallmark of many degenerative retinal diseases. The semi-synthetic tetracycline antibiotic, minocycline, appears to inhibit pro-inflammatory microglia which coincides with protection against photoreceptor cell degeneration. A sub-type of microglia termed disease associated microglia (DAM) have recently been associated with a wide range of central nervous system (CNS) diseases. In this study we examine the kinetics of microglia infiltration towards the outer retina of rhodopsin knockout mice (Rho-/-) by immunofluorescence, and undertake transcriptional and spatial localization analysis of markers for evidence of both homeostatic function and appearance of DAM. We demonstrate in the Rho-/- mice, IBA1+ and P2RY12+ microglia take on an activated morphology early in disease, prior to notable photoreceptor loss and are capable of infiltrating the subretinal space. Expression of lipid processing enzyme and DAM-marker lipoprotein lipase (LPL) is primarily observed only after microglia have traversed the ONL. Administration of minocycline to Rho-/- mice induced loss of phagocytic/DAM microglia in the outer retina in vivo coinciding with photoreceptor survival and amelioration of retinal degeneration. Overall, we show that minocycline suppresses many DAM markers, in particular those associated with lipid metabolism indicating that suppression of this process is one mechanism by which minocycline protects against inflammation induced photoreceptor cell death.

Decreased CSF1R Signaling and the Accumulation of Reticular Pseudo-Drusen?

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is caused by dominant-acting mutations in the gene colony-stimulating factor 1 receptor (CSF1R). It is an ultra-rare leukoencephalopathy that involves demyelination of white matter and early-onset dementia. It has been well validated that mutations in the kinase region of the gene cause decreased signaling of the receptor via its two cognate ligands interleukin-34 (IL-34) and colony-stimulating factor-1 (CSF-1). In this article, we report a thorough analysis of retinal integrity in a 48-year-old genetically diagnosed ALSP patient. We show that although the optic nerve, optic chiasm, and optic tracts are relatively preserved, the patient has visual field deficits likely due to optic radiation and/or cortical atrophy. Intriguingly, we report the appearance of inner retinal vascular leakage and the appearance of reticular pseudo-drusen (RPD)-like deposits. We propose that the early stages of RPD accumulation may be associated with an attenuated CSF-1 receptor signaling axis. [Ophthalmic Surg Lasers Imaging Retina. 2021;52:666-671.].

Colonic disease recurrence following proctectomy with end colostomy for anorectal Crohn's disease.

AIM: In patients with anorectal Crohn's disease, it remains uncertain whether a total proctocolectomy with end ileostomy or proctectomy with end colostomy should be recommended due to the unknown rate of disease recurrence in the remaining colon. METHODS: A retrospective review of all patients with a known diagnosis of Crohn's disease who underwent a proctectomy with end colostomy for distal Crohn's disease between January 1, 2010 and January 1, 2019 at two IBD referral centres was conducted. Data collected included patient demographics, surgical variables at the time of proctectomy, and postoperative clinical, endoscopic and surgical recurrence rates. RESULTS: A total of 63 patients were included; mean age was 47 years (SD 15 years) and 32 (50.8%) were female. The majority of patients underwent a proctectomy with end colostomy (n = 56; 88.9%) while the remaining seven patients (11.1%) underwent a proctectomy with end colostomy and concurrent ileocectomy. A total of 55 patients (87.3%) had proctitis, 51 (81%) had perianal fistulating disease, and 34 (54%) had anal canal stenosis or ulceration. Most patients had medically refractory disease (n = 54; 85.7%) versus neoplasia (n = 9; 14.3%). The median length of long-term follow-up was 17.7 months (IQR: 4.72, 38.7 months). During that time, 14 (22.2%) experienced clinical recurrence, 10 of 34 evaluated (29.4%) had endoscopic recurrence, and 3 (4.76%) required a completion total abdominal colectomy for recurrent medically refractory disease in the colon. CONCLUSION: Colonic recurrence remains low following proctectomy and descending colostomy suggesting this operative management strategy is reasonable in Crohn's patients with distal disease.

Single-cell analyses identify circulating anti-tumor CD8 T cells and markers for their enrichment.

The ability to monitor anti-tumor CD8+ T cell responses in the blood has tremendous therapeutic potential. Here, we used paired single-cell RNA and TCR sequencing to detect and characterize "tumor-matching" (TM) CD8+ T cells in the blood of mice with MC38 tumors or melanoma patients using the TCR as a molecular barcode. TM cells showed increased activation compared with nonmatching T cells in blood and were less exhausted than matching cells in tumors. Importantly, PD-1, which has been used to identify putative circulating anti-tumor CD8+ T cells, showed poor sensitivity for identifying TM cells. By leveraging the transcriptome, we identified candidate cell surface markers for TM cells in mice and patients and validated NKG2D, CD39, and CX3CR1 in mice. These data show that the TCR can be used to identify tumor-relevant cells for characterization, reveal unique transcriptional properties of TM cells, and develop marker panels for tracking and analysis of these cells.

No need to watch the clock: persistence during laparoscopic sigmoidectomy for diverticular disease.

BACKGROUND: Laparoscopic sigmoidectomy is the preferred approach in the elective surgical management of diverticulitis. However, it is unclear if the benefits of laparoscopy persist when operative times are prolonged. We aimed to investigate if the recovery benefits associated with laparoscopy are retained when operative times are long. METHODS: A retrospective review of a prospectively maintained database of patients who underwent elective laparoscopic sigmoidectomy from 2010-2015 at a single academic tertiary institution was performed. Operative times among laparoscopic completed cases were divided into quartiles, and patient outcomes were compared between the groups. RESULTS: A total of 466 patients (median age: 58 ± 11.6 years, 58% females) underwent sigmoidectomy: 430 completed laparoscopically and 36 (7.7%) converted. Median operative time in laparoscopically completed cases was 188 min (IQR 154-230). There were no differences in morbidity (P = 0.52) or readmission rates (P = 0.22) among the quartiles. The 2nd and 4th operative time quartiles were associated with significantly longer length of stay (LOS) when compared to the fastest quartile (P = 0.003 and P = 0.002, respectively), but there was no increase in LOS as operative times progressed between the 2nd, 3rd, and 4th quartiles. LOS after conversion was longer but did not reach statistical significance when compared to laparoscopically completed operations in the longest quartile (5.0 vs 6.5 days, P = 0.075) CONCLUSIONS: Our data do not support preemptive conversion of laparoscopic sigmoidectomy to avoid prolonged operative times. As long as progress is safely being made, surgeons are justified to continue pursuing laparoscopic completion.

When should we add a diverting loop ileostomy to laparoscopic ileocolic resection for primary Crohn's disease?

BACKGROUND: The aims of this study were to determine risk factors for morbidity associated with laparoscopic ileocolic resection (LICR) for Crohn's disease (CD) and whether the addition of a diverting ileostomy is associated with reduced morbidity. METHODS: Patients undergoing LICR for primary CD at our institution from 2005 to 2015 included in a prospectively maintained database were assessed. The decision to perform a diverting ileostomy was left at the discretion of the operating surgeon. Demographics, disease-related, and treatment-related variables were evaluated using univariate and multivariate analyses as possible factors associated with diverting ileostomy creation and 30-day perioperative septic complications (anastomotic leaks and/or abscess). Use of any immunosuppressive medication was defined as use of steroids, biologics, and immunomodulators either alone or in combination. RESULTS: For 409 patients, mortality was nil, overall morbidity rate was 40.6%, conversion rate 9.3%, and septic morbidity rate 7.6%. A diverting stoma was created in 22% of cases and was independently associated with BMI < 18.5 kg/m2 (P = 0.001), low serum albumin levels (P = 0.006), and longer operative time (P = 0.003). Use of any immunosuppressive medication was the only variable independently associated with septic complications, both in the overall population (OR 2.7, P = 0.036) and in the subgroup of undiverted patients (OR 3.1, P = 0.031). There was no association between septic morbidity and ileostomy creation, anastomotic configuration, penetrating disease, combined procedures (other resection or strictureplasty), BMI, albumin levels, and operative times. CONCLUSIONS: LICR is safe in selected cases of complex penetrating disease, including when combined procedures are necessary. Our data are unable to prove that a diverting stoma is associated with reduced morbidity.