Three-dimensional telesurgery and remote proctoring over a 5G network.

PURPOSE: To present 2 cases of vitreoretinal surgery performed on a three-dimensional (3D) heads-up display surgical platform with real-time transfer of 3D video over a fifth-generation (5G) cellular network. METHODS: An epiretinal membrane peel and tractional retinal detachment repair performed at Massachusetts Eye and Ear in April 2019 were broadcast live to the Verizon 5G Lab in Cambridge, MA. RESULTS: Both surgeries were successful. The heads-up digital surgery platform, combined with a 5G network, allowed telesurgical transfer of high-quality 3D vitreoretinal surgery with minimal degradation. Average end-to-end latency was 250 ms, and average round-trip latency was 16 ms. Fine surgical details were observed remotely by a proctoring surgeon and trainee, with real-time communication via mobile phone. CONCLUSIONS: This pilot study represents the first successful demonstration of vitreoretinal surgery transmitted over a 5G network. Telesurgery has the potential to enhance surgical education, provide intraoperative consultation and guidance from expert proctors, and improve patient outcomes, especially in remote and low-resource areas.

Endothelial activation is associated with intestinal epithelial injury, systemic inflammation and treatment regimen in children living with vertically acquired HIV-1 infection.

BACKGROUND: Premature development of cardiovascular disease in children living with HIV-1 (CLWH) may be associated with compromised gut barrier function, microbial translocation, immune activation, systemic inflammation and endothelial activation. Biomarkers of these pathways may provide insights into pathogenesis of atherosclerotic disease in CLWH. METHODS: This was a cross-sectional study of CLWH enrolled in the multicentre Early Pediatric Initiation-Canadian Child Cure Cohort (EPIC4 ) who were on antiretroviral therapy (ART) with undetectable viral load. Plasma biomarkers of intestinal epithelial injury [intestinal fatty acid binding protein-1 (IFABP)], systemic inflammation [tumour necrosis factor (TNF) and interleukin-6 (IL-6)] and endothelial activation [angiopoietin-2 (Ang2), soluble vascular endothelial growth factor-1 (sVEGFR1) and soluble endoglin (sEng)] were quantified by enzyme-linked immunosorbent assay. Correlation and factor analysis of biomarkers were used to examine associations between innate immune pathways. RESULTS: Among 90 CLWH, 16% of Ang2, 15% of sVEGFR1 and 23% of sEng levels were elevated relative to healthy historic controls. Pairwise rank correlations between the three markers of endothelial activation were statistically significant (ρ = 0.69, ρ = 0.61 and ρ = 0.65, P < 0.001 for all correlations). An endothelial activation index, derived by factor analysis of the three endothelial biomarkers, was correlated with TNF (ρ = 0.47, P < 0.001), IL-6 (ρ = 0.60, P < 0.001) and intestinal fatty acid binding protein-1 (ρ = 0.67, P < 0.001). Current or past treatment with ritonavir-boosted lopinavir (LPV/r) was associated with endothelial activation (odds ratio = 5.0, 95% CI: 1.7-17, P = 0.0020). CONCLUSIONS: Endothelial activation is prevalent in CLWH despite viral suppression with combination ART and is associated with intestinal epithelial injury, systemic inflammation and treatment with LPV/r.

CD200R deletion promotes a neutrophil niche for Francisella tularensis and increases infectious burden and mortality.

Pulmonary immune control is crucial for protection against pathogens. Here we identify a pathway that promotes host responses during pulmonary bacterial infection; the expression of CD200 receptor (CD200R), which is known to dampen pulmonary immune responses, promotes effective clearance of the lethal intracellular bacterium Francisella tularensis. We show that depletion of CD200R in mice increases in vitro and in vivo infectious burden. In vivo, CD200R deficiency leads to enhanced bacterial burden in neutrophils, suggesting CD200R normally limits the neutrophil niche for infection. Indeed, depletion of this neutrophil niche in CD200R-/- mice restores F. tularensis infection to levels seen in wild-type mice. Mechanistically, CD200R-deficient neutrophils display significantly reduced reactive oxygen species production (ROS), suggesting that CD200R-mediated ROS production in neutrophils is necessary for limiting F. tularensis colonisation and proliferation. Overall, our data show that CD200R promotes the antimicrobial properties of neutrophils and may represent a novel antibacterial therapeutic target.

Adjuvant bevacizumab for melanoma patients at high risk of recurrence: survival analysis of the AVAST-M trial.

Background: Bevacizumab is a recombinant humanised monoclonal antibody to vascular endothelial growth factor shown to improve survival in advanced solid cancers. We evaluated the role of adjuvant bevacizumab in melanoma patients at high risk of recurrence. Patients and methods: Patients with resected AJCC stage IIB, IIC and III cutaneous melanoma were randomised to receive either adjuvant bevacizumab (7.5 mg/kg i.v. 3 weekly for 1 year) or standard observation. The primary end point was detection of an 8% difference in 5-year overall survival (OS) rate; secondary end points included disease-free interval (DFI) and distant metastasis-free interval (DMFI). Tumour and blood were analysed for prognostic and predictive markers. Results: Patients (n=1343) recruited between 2007 and 2012 were predominantly stage III (73%), with median age 56 years (range 18-88 years). With 6.4-year median follow-up, 515 (38%) patients had died [254 (38%) bevacizumab; 261 (39%) observation]; 707 (53%) patients had disease recurrence [336 (50%) bevacizumab, 371 (55%) observation]. OS at 5 years was 64% for both groups [hazard ratio (HR) 0.98; 95% confidence interval (CI) 0.82-1.16, P = 0.78). At 5 years, 51% were disease free on bevacizumab versus 45% on observation (HR 0.85; 95% CI 0.74-0.99, P = 0.03), 58% were distant metastasis free on bevacizumab versus 54% on observation (HR 0.91; 95% CI 0.78-1.07, P = 0.25). Forty four percent of 682 melanomas assessed had a BRAFV600 mutation. In the observation arm, BRAF mutant patients had a trend towards poorer OS compared with BRAF wild-type patients (P = 0.06). BRAF mutation positivity trended towards better OS with bevacizumab (P = 0.21). Conclusions: Adjuvant bevacizumab after resection of high-risk melanoma improves DFI, but not OS. BRAF mutation status may predict for poorer OS untreated and potential benefit from bevacizumab. Clinical Trial Information: ISRCTN 81261306; EudraCT Number: 2006-005505-64.

The lymph nodes draining the small intestine and colon are anatomically separate and immunologically distinct.

Dendritic cells (DCs) in the small intestine (SI) and colon are fundamental to direct intestinal immune responses; they migrate to the mesenteric lymph nodes (MLNs) and prime T cells. We demonstrate anatomical segregation of lymphatic drainage from the intestine, specifically that DCs from the SI and colon migrate to different nodes within the MLN, here called the sMLN and cMLN. As a consequence, different frequencies of DC subsets observed in the SI and colon are reflected among the DCs in the sMLN and cMLN. Consistent with the SI's function in absorbing food, fed antigen is presented in the sMLN, but not in the cMLN. Furthermore, the levels of expression of CCR9 and α4ß7 are increased on T cells in the sMLN compared with the cMLN. DCs from the cMLN and colon are unable to metabolize vitamin A to retinoic acid (RA); thus, DCs may contribute to the differential expression of tissue homing markers observed in the sMLN and cMLN. In summary, the sMLN and cMLN, and the DCs that migrate to these LNs are anatomically and immunologically separate. This segregation allows immune responses in the SI and colon to be controlled independently.

Treatment outcomes after 3 years in neovascular age-related macular degeneration using a treat-and-extend regimen.

PURPOSE: To determine 3-year treatment outcomes after 1 to 3 years of ranibizumab or bevacizumab therapy using a treat-and-extend regimen in patients with neovascular age-related macular degeneration (AMD). DESIGN: Retrospective, interventional, consecutive case series. METHODS: We treated 212 eyes from 196 patients diagnosed with treatment-naive neovascular AMD between January 2009 and March 2013; they were treated with either ranibizumab or bevacizumab for a minimum of 1 year, using a treat-and-extend regimen. The main outcome measures were change from baseline best-corrected Snellen visual acuity (BCVA), proportion of eyes losing <3 BCVA lines, proportion of eyes gaining ≥ 3 BCVA lines, change from baseline central retinal thickness, and mean number of injections at 1, 2 and 3 years of follow-up. RESULTS: The mean follow-up period was 1.88 years (median, 2 years). At baseline, mean BCVA was 20/139; it improved to 20/79 (P < 0.001) after 1 year of treatment and was maintained at 20/69 and 20/64 at 2 and 3 years follow-up (P < 0.001), respectively. At baseline, mean central retinal thickness was 351 µm and significantly decreased to 285 µm, 275 µm and 276 µm at 1, 2 and 3 years of follow-up (P < 0.001), respectively. Patients received, on average, 7.6, 5.7 and 5.8 injections over years 1, 2 and 3 of treatment, respectively. At final follow-up, 94% of eyes had lost <3 lines BCVA, and 34.4% of eyes had gained ≥ 3 lines BCVA. CONCLUSIONS: The treat-and-extend regimen is effective in achieving and maintaining visual and anatomic improvements in patients with neovascular AMD for up to 3 years of treatment.

Lymph-borne CD8α+ dendritic cells are uniquely able to cross-prime CD8+ T cells with antigen acquired from intestinal epithelial cells.

Cross-presentation of cellular antigens is crucial for priming CD8(+) T cells, and generating immunity to intracellular pathogens--particularly viruses. It is unclear which intestinal phagocytes perform this function in vivo. To address this, we examined dendritic cells (DCs) from the intestinal lymph of IFABP-tOVA 232-4 mice, which express ovalbumin in small intestinal epithelial cells (IECs). Among lymph DCs (LDCs) only CD103(+) CD11b(-) CD8α(+) DCs cross-present IEC-derived ovalbumin to CD8(+) OT-I T cells. Similarly, in the mesenteric lymph nodes (MLNs), cross-presentation of IEC-ovalbumin was limited to the CD11c(+) MHCII(hi) CD8α(+) migratory DCs, but absent from all other subsets, including the resident CD8α(hi) DCs. Crucially, delivery of purified CD8α(+) LDCs, but not other LDC subsets, into the MLN subcapsular lymphatic sinus induced proliferation of ovalbumin-specific, gut-tropic CD8(+) T cells in vivo. Finally, in 232-4 mice treated with R848, CD8α(+) LDCs were uniquely able to cross-prime interferon γ-producing CD8(+) T cells and drive their migration to the intestine. Our results clearly demonstrate that migrating CD8α(+) intestinal DCs are indispensable for cross-presentation of cellular antigens and, in conditions of inflammation, for the initial differentiation of effector CD8(+) T cells. They may therefore represent an important target for the development of antiviral vaccinations.

Intravitreal and subconjunctival melphalan for retinoblastoma in transgenic mice.

Purpose. To measure the chemotherapeutic effects of focal melphalan (intravitreal and subconjunctival) on tumor burden, hypoxia, and vasculature in LHBETATAG murine retinoblastoma model. Methods. LHBETATAG transgenic mice were treated with a single 1 mcg intravitreal injection of melphalan, 100 mcg subconjunctival injection, or semiweekly 10 mcg subconjunctival injections for 3 weeks. At 1 or 3 weeks, eyes were enucleated, serially sectioned, and processed with haematoxylin and eosin (H&E) for tumor burden measurements and probed with immunofluorescence to analyze tumor hypoxia and vasculature. Results. Focal melphalan significantly reduced retinal tumor size (P < 0.02) when given intravitreally or subconjunctivally. Eyes treated with a one-time intravitreal injection of 1 mcg melphalan had significantly smaller tumors at both 1 week (P = 0.017) and at 3 weeks after injection (P = 0.005). Intratumoral hypoxia showed a significant decline in hypoxia at 1 week following intravitreal injection and after maximum dosage of subconjunctival melphalan. Total vasculature was not significantly affected following intravitreal administration. Conclusion. Focal delivery of melphalan via intravitreal or subconjunctival injection has a significant effect on reducing tumor burden, hypoxia, and vasculature, in the treatment of murine retinoblastoma tumors.

Interleukin-22 binding protein (IL-22BP) is constitutively expressed by a subset of conventional dendritic cells and is strongly induced by retinoic acid.

Interleukin-22 (IL-22) is mainly produced at barrier surfaces by T cells and innate lymphoid cells and is crucial to maintain epithelial integrity. However, dysregulated IL-22 action leads to deleterious inflammation and is involved in diseases such as psoriasis, intestinal inflammation, and cancer. IL-22 binding protein (IL-22BP) is a soluble inhibitory IL-22 receptor and may represent a crucial regulator of IL-22. We show both in rats and mice that, in the steady state, the main source of IL-22BP is constituted by a subset of conventional dendritic cells (DCs) in lymphoid and non-lymphoid tissues. In mouse intestine, IL-22BP was specifically expressed in lamina propria CD103(+)CD11b(+) DC. In humans, IL-22BP was expressed in immature monocyte-derived DC and strongly induced by retinoic acid but dramatically reduced upon maturation. Our data suggest that a subset of immature DCs may actively participate in the regulation of IL-22 activity in the gut by producing high levels of IL-22BP.

Intestinal CD103(-) dendritic cells migrate in lymph and prime effector T cells.

Intestinal dendritic cells (DCs) continuously migrate through lymphatics to mesenteric lymph nodes where they initiate immunity or tolerance. Recent research has focused on populations of intestinal DCs expressing CD103. Here we demonstrate, for the first time, the presence of two distinct CD103(-) DC subsets in intestinal lymph. Similar to CD103(+) DCs, these intestine-derived CD103(-) DCs are responsive to Flt3 and they efficiently prime and confer a gut-homing phenotype to naive T cells. However, uniquely among intestinal DCs, CD103(-) CD11b(+) CX(3)CR1(int) lymph DCs induce the differentiation of both interferon-γ and interleukin-17-producing effector T cells, even in the absence of overt stimulation. Priming by CD103(-) CD11b(+) DCs represents a novel mechanism for the rapid generation of effector T-cell responses in the gut. Therefore, these cells may prove to be valuable targets for the treatment of intestinal inflammation or in the development of effective oral vaccines.

Transcriptional signatures mediated by acetylation overlap with early-stage Alzheimer's disease.

The mechanisms by which environmental influences lead to the development of complex neurodegenerative diseases are largely unknown. It is known, however, that epigenetic mechanisms can mediate alterations in transcription due to environmental influences. In order to identify genes susceptible to regulation in the adult cortex by one type of epigenetic mechanism, histone, and protein acetylation, we treated mice with the histone deacetylase inhibitor Trichostatin A (TSA). After 1 week of treatment with TSA, RNA was extracted from the brain cortices of mice and gene expression differences were analyzed by microarray profiling. The altered genes were then compared with genes differentially expressed in microarray studies of disease by database and literature searches. Genes regulated by TSA were found to significantly overlap with differentially expressed genes in the Alzheimer's disease (AD) brain. Several TSA-regulated genes involved in chromatin remodeling and epigenetic reprogramming including histone cluster 1, H4 h (Hist1H4 h), methionine adenosyltransferase II, alpha (Mat2a), and 5-methyltetrahydrofolate homocysteine reductase (Mtrr) overlapped with genes altered in early-stage AD in gray matter. We also show that the expression of hemoglobin, which has been shown to be altered in neurons in the AD brain, is regulated by TSA treatment. This analysis suggests involvement of epigenetic mechanisms in neurons in early stages of AD.

Prolonged survival after surgical management of metastases in malignant melanoma: three case reports.

The incidence of malignant melanoma is increasing and the management of metastatic disease remains a challenge to clinicians. We describe three cases where surgical management of metastases has resulted in prolonged survival.

Safety of zoledronic acid and incidence of osteonecrosis of the jaw (ONJ) during adjuvant therapy in a randomised phase III trial (AZURE: BIG 01-04) for women with stage II/III breast cancer.

The AZURE trial is an ongoing phase III, academic, multi-centre, randomised trial designed to evaluate the role of zoledronic acid (ZOL) in the adjuvant therapy of women with stage II/III breast cancer. Here, we report the safety and tolerability profile of ZOL in this setting. Eligible patients received (neo)adjuvant chemotherapy and/or endocrine therapy and were randomised to receive neither additional treatment nor intravenous ZOL 4 mg. ZOL was administered after each chemotherapy cycle to exploit potential sequence-dependent synergy. ZOL was continued for 60 months post-randomisation (six doses in the first 6 months, eight doses in the following 24 months and five doses in the final 30 months). Serious (SAE) and non-serious adverse event (AE) data generated during the first 36 months on study were analysed for the safety population. 3,360 patients were recruited to the AZURE trial. The safety population comprised 3,340 patients (ZOL 1,665; control 1,675). The addition of ZOL to standard treatment did not significantly impact on chemotherapy delivery. SAE were similar in both treatment arms. No significant safety differences were seen apart from the occurrence of osteonecrosis of the jaw (ONJ) in the ZOL group (11 confirmed cases; 0.7%; 95% confidence interval 0.3-1.1%). ZOL in the adjuvant setting is well tolerated, and can be safely administered in addition to adjuvant therapy including chemotherapy. The adverse events were consistent with the known safety profile of ZOL, with a low incidence of ONJ.

Rates of initial virological suppression and subsequent virological failure after initiating highly active antiretroviral therapy: the impact of aboriginal ethnicity and injection drug use.

OBJECTIVES: To compare rates of initial virological suppression and subsequent virological failure by Aboriginal ethnicity after starting highly active antiretroviral therapy (HAART). METHODS: We conducted a retrospective cohort study of antiretroviral-naïve HIV-patients starting HAART in January 1999-June 2005 (baseline), followed until December 31, 2005 in Alberta, Canada. We compared the odds of achieving initial virological suppression (viral load <500 copies/mL) by Aboriginal ethnicity using logistic regression and, among those achieving suppression, rates of virological failure (the first of two consecutive viral loads >1000 copies/mL) by Aboriginal ethnicity using cumulative incidence curves and Cox proportional hazards models. Sex, injection drug use as an HIV exposure category (IDU), baseline age, CD4 cell count, viral load, calendar year, and HAART regimen were considered as potential confounders. RESULTS: Of 461 study patients, 37% were Aboriginal and 48% were IDUs; 71% achieved initial virological suppression and were followed for 730.4 person-years. After adjusting for confounding variables, compared to non-Aboriginals with other exposures, the odds of achieving initial virological suppression were lower for Aboriginal IDUs (odds ratio (OR)=0.33, 95% CI=0.19-0.60, p=0.0002), non-Aboriginal IDUs (OR=0.30, 95% CI=0.15-0.60, p=0.0006), and Aboriginals with other exposures (OR=0.38, 95% CI=0.21-0.67, p=0.0009). Among those achieving suppression, Aboriginals experienced higher virological failure rates ≥1 year after suppression (hazard ratio=3.35, 95% CI=1.68-6.65, p=0.0006). CONCLUSIONS: Future research should investigate adherence among Aboriginals and IDUs treated with HAART and explore their treatment experiences to assess ways to improve outcomes.

Renal function changes and NHS resource use in breast cancer patients with metastatic bone disease treated with IV zoledronic acid or oral ibandronic acid: a four-centre non-interventional study.

AIMS: To describe renal function monitoring practice in patients with metastatic bone disease (MBD) treated with IV zoledronic acid (ZA) and oral ibandronic acid (IA), the management pathways and NHS hospital resources used. METHODS: Medical records of 189 patients; IA (91), ZA (98) with primary breast cancer and MBD were reviewed, and data collected on renal monitoring and hospital visits during bisphosphonate therapy. Time and motion review of resources to administer the bisphosphonates was also conducted. RESULTS: Only 30% of patients given ZA and no patient given IA had baseline creatinine clearance (CrCl) recorded. Calculated baseline CrCl suggested impaired renal function in 33% ZA and 29% IA patients. Dose reductions were not made correctly in 29 ZA and 2 IA patients whose monitoring suggested it. ZA patients made more clinic and day care attendances than IA-treated patients, at twice the cost. Staff activity and patient time per visit was higher with ZA than IA. CONCLUSION: Although limited by retrospective design, these results demonstrate that in many patients, CrCl is not calculated before or during treatment with bisphosphonates. Renal function deteriorated in many patients during therapy. In view of these effects, practice should be reviewed to ensure appropriate dosing.

Bilateral massive retinal gliosis associated with retinopathy of prematurity.

Massive retinal gliosis (MRG) is a rare, benign intraocular condition that may develop in association with long-standing eye conditions including chronic inflammation, vascular disorders, glaucoma, trauma, or congenital abnormalities. It is thought to represent a nonneoplastic reactive tissue response to retinal injury. Here, we describe an unusual case of bilateral MRG in association with retinopathy of prematurity. To our knowledge, this may be the first report of such an occurrence. The differential diagnosis of MRG is discussed with specific emphasis on its relationship to vasoproliferative tumor of the retina and presumed acquired retinal hemangiomas. In addition, we hypothesize that MRG, vasoproliferative tumor of the retina, and presumed acquired retinal hemangiomas may represent different phenotypes along a spectrum of the same disease process.

Pulmonary zygomycosis in solid organ transplant recipients in the current era.

Fifty-eight solid organ transplant recipients with zygomycosis were studied to assess the presentation, radiographic characteristics, risks for extra-pulmonary dissemination and mortality of pulmonary zygomycosis. Pulmonary zygomycosis was documented in 31 patients (53%) and developed a median of 5.5 months (interquartile range, 2-11 months) posttransplantation. In all, 74.2% (23/31) of the patients had zygomycosis limited to the lungs and 25.8% (8/31) had lung disease as part of disseminated zygomycosis; cutaneous/soft tissue (50%, 4/8) was the most common site of dissemination. Pulmonary disease presented most frequently as consolidation/mass lesions (29.0%), nodules (25.8%) and cavities (22.6%). Patients with disseminated disease were more likely to have Mycocladus corymbifer as the causative pathogen. The mortality rate at 90 days after the treatment was 45.2%. In summary, pulmonary zygomycosis is the most common manifestation in solid organ transplant recipients with zygomycosis, and disseminated disease often involves the cutaneous/soft tissue sites but not the brain.

Neurologic immune reconstitution inflammatory syndrome in HIV/AIDS: outcome and epidemiology.

OBJECTIVE: To characterize the immune reconstitution inflammatory syndrome in the nervous system (NeuroIRIS) among patients with HIV/AIDS. BACKGROUND: NeuroIRIS has been recognized as a complication of combination antiretroviral therapy (cART). METHODS: A retrospective analysis was performed of NeuroIRIS patients fulfilling diagnostic criteria and followed at the Northern or Southern Alberta (HIV) Clinics. A nested epidemiologic study was performed within a subset of patients in whom cART was started from 1999 to 2007. RESULTS: NeuroIRIS was diagnosed in seven patients initiating cART. All were men (median age, 35 years) and exhibited severe immunosuppression (median CD4(+) T cells, 30 cells/mm(3)). Four patients presented to the Southern Alberta Clinic, representing all NeuroIRIS cases among 461 patients in whom cART was initiated over an 8-year period (incidence 0.9%). New onset of neurologic deterioration (n = 4) or worsening of prior neurologic disabilities (n = 3) due to progressive multifocal leukoencephalopathy, toxoplasmic encephalitis, and cryptococcal meningitis occurred between 2 to 25 weeks after the initiation of cART. All patients demonstrated a robust increase in blood CD4(+) T-cell count in response to cART. A brain biopsy in one patient revealed inflammation and necrosis together with CD68(+) macrophage and CD8(+) T-cell infiltrates, which were also CD40 and CD154 immunoreactive. Two patients received corticosteroids as treatment for NeuroIRIS with an overall survival of 86%, while 14% exhibited fixed neurologic disabilities. CONCLUSIONS: Immune reconstitution inflammatory syndrome in the nervous system (NeuroIRIS) remains an uncommon complication of combination antiretroviral therapy (cART) but with a potentially poor outcome. Initiation of cART in very immunosuppressed patients requires close monitoring to manage NeuroIRIS in an expedient manner.