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Neovascular age-related macular degeneration (nAMD) is a leading cause of blindness with several intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents available for its management such as aflibercept, bevacizumab, and ranibizumab. However, direct comparisons between these three agents among the same patient population are limited. To assess the rate and growth of complete retinal pigment epithelium and outer retinal atrophy (cRORA) in eyes with nAMD treated with aflibercept, bevacizumab, and/or ranibizumab. Retrospective cohort study of patients with treatment-naïve neovascular AMD seen at an academic hospital between October 2006 and February 2019. Study eyes were treated with intravitreal injections of aflibercept, bevacizumab, and/or ranibizumab and followed for two years. cRORA prevalence, location, size, and growth rate. Eyes were imaged with Cirrus spectral domain optical coherence tomography (SD-OCT). Presence and size of cRORA were calculated using the FDA-approved Advanced RPE Analysis software. Linear regression models were used to correlate cRORA progression with baseline demographic and ocular characteristics, anti-VEGF drug, and number of injections. Unpaired t-tests, ANOVA, and linear regression models were computed with SAS 9.4. 197 eyes from 158 patients (mean age 78.9, 62.9% women) received an average of 13 anti-VEGF injections over 24 months. 22% developed new cRORA. Mean cRORA area increased from 1.71 mm2 to 2.93 mm2. At 24 months, eyes with 11+ injections had significantly less cRORA area (11+ injections, 4.02 mm2; ≤ 10 injections, 2.46 mm2; p = 0.01) and growth rate (11+ injections, 0.41 mm2/year; ≤ 10 injections, 1.05 mm2/year; p = 0.02). Choice of anti-VEGF drug yielded no significant difference in cRORA progression. Treating nAMD with aflibercept, bevacizumab or ranibizumab demonstrated comparable cRORA development at 24 months. Number of injections inversely correlated with cRORA area and growth. These results warrant further investigation in the pathophysiology of cRORA in anti-VEGF treated eyes.

ObjectiveTo assess the dose-dependent relationship between smoking history and cancer screening rates or staging of cancer diagnoses.DesignProspective, population-based cohort study.SettingQuestionnaire responses from the Women’s Health Initiative (WHI) Observational Study.Participants89 058 postmenopausal women.Outcome measuresLogistic regression models were used to assess the odds of obtaining breast, cervical, and colorectal cancer screening as stratified by smoking status. The odds of late-stage cancer diagnoses among patients with adequate vs inadequate screening as stratified by smoking status were also calculated.ResultsOf the 89 058 women who participated, 52.8% were never smokers, 40.8% were former smokers, and 6.37% were current smokers. Over an average of 8.8 years of follow-up, current smokers had lower odds of obtaining breast (OR 0.55; 95% CI 0.51 to 0.59), cervical (OR 0.53; 95% CI 0.47 to 0.59), and colorectal cancer (OR 0.71; 95% CI 0.66 to 0.76) screening compared with never smokers. Former smokers were more likely than never smokers to receive regular screening services. Failure to adhere to screening guidelines resulted in diagnoses at higher cancer stages among current smokers for breast cancer (OR 2.78; 95% CI 1.64 to 4.70) and colorectal cancer (OR 2.26; 95% CI 1.01 to 5.05).ConclusionsActive smoking is strongly associated with decreased use of cancer screening services and more advanced cancer stage at the time of diagnosis. Clinicians should emphasise the promotion of both smoking cessation and cancer screening for this high-risk group.

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness among the elderly in developed countries. Subthreshold retinal laser therapy is a new technique that targets drusen - a marker of nonexudative AMD - without causing incidental retinal damage associated with conventional laser photocoagulation. This review summarizes published literature on subthreshold retinal laser therapy as prophylactic treatment of nonexudative AMD. A literature search of the PubMed, Medline, and Embase databases was conducted from January 1997 to April 2018. Studies were analyzed based upon study design, laser parameters, drusen reduction, changes in visual acuity (VA), and the development of choroidal neovascularization (CNV) and/or geographic atrophy (GA). Twelve studies involving 2,481 eyes treated with subthreshold retinal laser therapy were included in this review. Treatment led to increased drusen reduction, and studies with significant VA improvement were associated with significant drusen reduction. There was no significant change in the risk of developing CNV or GA. Subthreshold retinal laser therapy is effective for reducing drusen and potentially improving vision in patients with nonexudative AMD. This therapy does not show benefits in reducing development of CNV or GA. Thus, its long-term efficacy to prevent progression to advanced AMD cannot yet be recommended. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:e61-e70.].

Integrated photodetectors are essential components of scalable photonics platforms for quantum and classical applications. However, most efforts in the development of such devices to date have been focused on infrared telecommunications wavelengths. Here, we report the first monolithically integrated avalanche photodetector (APD) for visible light. Our devices are based on a doped silicon rib waveguide with a novel end-fire input coupling to a silicon nitride waveguide. We demonstrate a high gain-bandwidth product of 234 ± 25 GHz at 20 V reverse bias measured for 685 nm input light, with a low dark current of 0.12 μA. We also observe open eye diagrams at up to 56 Gbps. This performance is very competitive when benchmarked against other integrated APDs operating in the infrared range. With CMOS-compatible fabrication and integrability with silicon photonic platforms, our devices are attractive for sensing, imaging, communications, and quantum applications at visible wavelengths. Integrated photodetectors are essential for scalable photonic platforms, yet most efforts are concerted on the developing devices operating at infrared telecommunication wavelengths. Here, the authors report a monolithically integrated avalanche photodetector for visible light based on doped-Si rib waveguide with end-fire input coupling to a silicon nitride waveguide.

Rehabilitation is important for regaining mobility poststroke. Clinical practice guidelines suggest a high number of repetitive stepping activities to optimize subacute recovery especially when undertaken at intensities that challenge cardiovascular fitness. However, adherence to these guidelines is unclear. The objective of this study was to quantify aerobic minutes and step number in usual care inpatient stroke rehabilitation unit physical therapy sessions across Canada and identify characteristics of participants who met guideline aerobic intensity minutes at a session midpoint in their rehabilitation. To gain insight into usual care, we analyzed cross-sectional data from the usual care arm of the Walk 'n Watch implementation trial; trial sites included Canadian rehabilitation units that were not typically involved in research studies. To be included, medically stable patients were admitted for inpatient stroke rehabilitation, and able to take > 5 steps with a maximum of one person assisting. We assessed a midpoint physical therapy session with a wrist-based heart monitor (aerobic minutes) and ankle-based step counter (step number). Means, histograms, and correlations between aerobic minutes (> 40% heart rate reserve) and steps were calculated. There were 166 participants (69 females, age 69 standard deviation (SD)12 years) with stroke (138 Ischemic/ 27 Hemorrhagic) included. Participants had a mean of 10(SD11) aerobic minutes and 985(SD579) steps. The relationship between step number and aerobic minutes was negligible (R2 = 0.003). More participants with ≥20 aerobic minutes in a session were male, with lower 6 Minute Walk Test distance, and have a subcortical stroke location. The number of steps has increased, but aerobic minutes has not changed and remains extremely low compared to published reports in the past several years. Given that increasing activity levels are critical for stroke recovery, further investigation into the potential barriers to achieving targets set by guidelines is recommended. ClinicalTrials.gov NCT04238260.

Retinal vein occlusion is the second-leading cause of vision loss by retinal vascular disease. Subthreshold micropulse laser therapy (SLT) is safer than conventional laser photocoagulation (CLP), yet existing reviews of its use for branch retinal vein occlusion (BRVO) are limited in scope. A literature search of PubMed, Google Scholar, Embase, Cochrane Library and ClinicalTrials.gov databases was conducted in August 2019 without restriction on language or publication date. Outcomes included changes in macular oedema (ME) and visual acuity (VA), and rates of complications or retreatments. Fourteen studies involving 315–405 eyes diagnosed with BRVO were evaluated. Treatment with SLT is associated with significant and durable reduction of ME and VzA as early as 1 month. SLT performs comparably with conventional photocoagulation and intravitreal injections (IVIs) of ranibizumab. Subthreshold laser therapy is safer and as effective as CLP for the treatment of ME associated with BRVO. SLT may be used in combination with anti-VEGF IVIs to enhance improvement in VA and ME resolution.

Yeast central carbon metabolism has been engineered to achieve a more efficient isoprenoid biosynthesis pathway, an advance that brings commodity-scale production of such compounds a step closer. A yeast for efficient isoprenoid manufacture These authors have re-engineered the central carbon metabolism of Saccharomyces cerevisiae to improve redox balance and eliminate carbon and energy waste associated with acetyl-CoA biosynthesis. The resulting strains can produce the acetyl-CoA-based hydrocarbon β-farnesene—an important precursor to many fragrances, fuels and therapeutics—in greater quantities than the starting yeast strain while consuming less oxygen. Cultures can be grown effectively in 200,000-litre industrial bioreactors. This system points the way towards a platform for high-productivity, feedstock-efficient production for all isoprenoids and other acetyl-CoA-derived compounds. A bio-based economy has the potential to provide sustainable substitutes for petroleum-based products and new chemical building blocks for advanced materials. We previously engineered Saccharomyces cerevisiae for industrial production of the isoprenoid artemisinic acid for use in antimalarial treatments 1 . Adapting these strains for biosynthesis of other isoprenoids such as β-farnesene (C 15 H 24 ), a plant sesquiterpene with versatile industrial applications 2 , 3 , 4 , 5 , is straightforward. However, S. cerevisiae uses a chemically inefficient pathway for isoprenoid biosynthesis, resulting in yield and productivity limitations incompatible with commodity-scale production. Here we use four non-native metabolic reactions to rewire central carbon metabolism in S. cerevisiae, enabling biosynthesis of cytosolic acetyl coenzyme A (acetyl-CoA, the two-carbon isoprenoid precursor) with a reduced ATP requirement, reduced loss of carbon to CO 2 -emitting reactions, and improved pathway redox balance. We show that strains with rewired central metabolism can devote an identical quantity of sugar to farnesene production as control strains, yet produce 25% more farnesene with that sugar while requiring 75% less oxygen. These changes lower feedstock costs and dramatically increase productivity in industrial fermentations which are by necessity oxygen-constrained 6 . Despite altering key regulatory nodes, engineered strains grow robustly under taxing industrial conditions, maintaining stable yield for two weeks in broth that reaches >15% farnesene by volume. This illustrates that rewiring yeast central metabolism is a viable strategy for cost-effective, large-scale production of acetyl-CoA-derived molecules.

Although clinical guidelines support high repetitions of walking after stroke, practice is slow to change. We undertook an implementation trial to enable entire stroke units to use the Walk ‘n Watch structured, progressive exercise protocol. Our objective was to evaluate the effectiveness of the Walk ‘n Watch implementation package on patient outcomes after 4 weeks in an inpatient stroke rehabilitation setting. This pragmatic phase 3, stepped-wedge, cluster-randomised controlled trial took place in 12 sites (inpatient stroke rehabilitation units) across seven Canadian provinces. Each site was randomly allocated (1:1:1:1) to one of four transition sequences with three sites in each sequence. Sites changed practice from usual care to Walk ‘n Watch at different times according to their allocation. All front-line physical therapists were trained to deliver the Walk ‘n Watch protocol. Walk ‘n Watch required completion of a minimum of 30 min of walking-related activities per session, which progressively increased in intensity based on heart rate and step count monitors. Progressions were prescribed on the basis of a screening 6-minute walk test (6MWT) done by the front-line physical therapist as part of the protocol. The primary endpoint was walking endurance (6MWT) at 4 weeks after randomisation. Masked assessors completed evaluations at baseline and 4 weeks later. The primary analysis used a linear mixed-effects model adjusted for unit size, stratum, calendar time, age, sex, and baseline 6MWT. This trial is registered with ClinicalTrials.gov, NCT04238260, and is complete. Between June 4, 2021, and March 1, 2024, we enrolled 12 sites with 314 participants, of whom eight were deemed ineligible after enrolment and 306 were included in the primary analysis (162 in the usual care group, 144 in the Walk ‘n Watch group). Participants had a mean age of 68 years (SD 13), a mean time since stroke of 29 days (17), and a baseline 6MWT of 152 m (106). 188 (61%) were male and 118 (39%) were female. The mean 6MWT in the usual care group was 137·1 m (100·9) at baseline and 223·6 m (130·4) after 4 weeks. The mean 6MWT in the Walk ‘n Watch group was 163·6 m (112·7) at baseline and 297·2 m (133·2) after 4 weeks. The 6MWT improvement was 43·6 m (95% CI 12·7–76·1) greater in the Walk ‘n Watch group than in the usual care group. No serious adverse events occurred during a Walk ‘n Watch session. Nine serious adverse events were reported and required admission to acute care (four were recorded in the usual care group and five in the Walk ‘n Watch group). The Walk ‘n Watch protocol resulted in a clinically meaningful improvement in walking endurance in patients with subacute stroke in a real-world setting. The protocol can be readily implemented into practice with minimal additional resources. Further research is needed to identify characteristics of patients who might benefit the most from Walk ‘n Watch. Canadian Institutes of Health Research, Canada Brain Research Fund, Michael Smith Health Research BC, Fonds de recherche du Québec-Santé, Canada Research Program, and Heart and Stroke Foundation of Canada.

Cibisatamab is a bispecific antibody-based construct targeting carcinoembryonic antigen (CEA) on tumour cells and CD3 epsilon chain as a T-cell engager. Here we evaluated cibisatamab for advanced CEA-positive solid tumours in two open-label Phase 1 dose-escalation and -expansion studies: as a single agent with or without obinutuzumab in S1 (NCT02324257) and with atezolizumab in S2 (NCT02650713). Primary endpoints were safety, dose finding, and pharmacokinetics in S1; safety and dose finding in S2. Secondary endpoints were anti-tumour activity (including overall response rate, ORR) and pharmacodynamics in S1; anti-tumour activity, pharmacodynamics and pharmacokinetics in S2. S1 and S2 enrolled a total of 149 and 228 patients, respectively. Grade ≥3 cibisatamab-related adverse events occurred in 36% of S1 and 49% of S2 patients. The ORR was 4% in S1 and 7% in S2. In S2, patients with microsatellite stable colorectal carcinoma (MSS-CRC) given flat doses of cibisatamab and atezolizumab demonstrated an ORR of 14%. In S1 and S2, 40% and 52% of patients, respectively, developed persistent anti-drug antibodies (ADAs). ADA appearance could be mitigated by obinutuzumab-pretreatment, with 8% of patients having persistent ADAs. Overall, cibisatamab warrants further exploration in immunotherapy combination strategies for MSS-CRC. Cibisatamab is a T-cell bispecific antibody targeting the carcinoembryonic antigen (CEA) on tumor cells and CD3 epsilon chain on T cells. Here the authors report the results of two clinical trials of cibisatamab as monotherapy (NCT02324257) and in combination with atezolizumab (anti-PD-L1; NCT02650713) in patients with CEA-positive solid tumors.

We sought to examine whether type 2 diabetes increases the risk of acute organ dysfunction and of hospital mortality following severe sepsis that requires admission to an intensive care unit (ICU). Nationwide population-based retrospective cohort study of 16,497 subjects with severe sepsis who had been admitted for the first time to an ICU during the period of 1998-2008. A diabetic cohort (n = 4573) and a non-diabetic cohort (n = 11924) were then created. Relative risk (RR) of organ dysfunctions, length of hospital stay (LOS), 90-days hospital mortality, ICU resource utilization and hazard ratio (HR) of mortality adjusted for age, gender, Charlson-Deyo comorbidity index score, surgical condition and number of acute organ dysfunction, were compared across patients with severe sepsis with or without diabetes. Diabetic patients with sepsis had a higher risk of developing acute kidney injury (RR, 1.54; 95% confidence interval (CI), 1.44-1.63) and were more likely to be undergoing hemodialysis (15.55% vs. 7.24%) in the ICU. However, the diabetic cohort had a lower risk of developing acute respiratory dysfunction (RR = 0.96, 0.94-0.97), hematological dysfunction (RR = 0.70, 0.56-0.89), and hepatic dysfunction (RR = 0.77, 0.63-0.93). In terms of adjusted HR for 90-days hospital mortality, the diabetic patients with severe sepsis did not fare significantly worse when afflicted with cardiovascular, respiratory, hepatic, renal and/or neurologic organ dysfunction and by numbers of organ dysfunction. There was no statistically significant difference in LOS between the two cohorts (median 17 vs. 16 days, interquartile range (IQR) 8-30 days, p = 0.11). Multiple logistic regression analysis to predict the occurrence of mortality shows that being diabetic was not a predictive factor with an odds ratio of 0.972, 95% CI 0.890-1.061, p = 0.5203. This large nationwide population-based cohort study suggests that diabetic patients do not fare worse than non-diabetic patients when suffering from severe sepsis that requires ICU admission.