Collaborating in the Time of COVID-19: The Scope and Scale of Innovative Responses to a Global Pandemic.

The emergence of COVID-19 spurred the formation of myriad teams to tackle every conceivable aspect of the virus and thwart its spread. Enabled by global digital connectedness, collaboration has become a constant theme throughout the pandemic, resulting in the expedition of the scientific process (including vaccine development), rapid consolidation of global outbreak data and statistics, and experimentation with novel partnerships. To document the evolution of these collaborative efforts, the authors collected illustrative examples as the pandemic unfolded, supplemented with publications from the JMIR COVID-19 Special Issue. Over 60 projects rooted in collaboration are categorized into five main themes: knowledge dissemination, data propagation, crowdsourcing, artificial intelligence, and hardware design and development. They highlight the numerous ways that citizens, industry professionals, researchers, and academics have come together worldwide to consolidate information and produce products to combat the COVID-19 pandemic. Initially, researchers and citizen scientists scrambled to access quality data within an overwhelming quantity of information. As global curated data sets emerged, derivative works such as visualizations or models were developed that depended on consistent data and would fail when there were unanticipated changes. Crowdsourcing was used to collect and analyze data, aid in contact tracing, and produce personal protective equipment by sharing open designs for 3D printing. An international consortium of entrepreneurs and researchers created a ventilator based on an open-source design. A coalition of nongovernmental organizations and governmental organizations, led by the White House Office of Science and Technology Policy, created a shared open resource of over 200,000 research publications about COVID-19 and subsequently offered cash prizes for the best solutions to 17 key questions involving artificial intelligence. A thread of collaboration weaved throughout the pandemic response, which will shape future efforts. Novel partnerships will cross boundaries to create better processes, products, and solutions to consequential societal challenges.

Thoracofemoral bypass outcomes in the Vascular Quality Initiative.

OBJECTIVE: Thoracofemoral bypass (TFB) has been used infrequently but is an alternative for select patients with aortoiliac occlusive disease. Limited data are available in the reported data regarding TFB, with all studies small, single-center series. We aimed to describe the perioperative and long-term survival, patency, and rate of major perioperative complications after TFB in a large national registry. METHODS: The Vascular Quality Initiative suprainguinal bypass module was used to identify patients who had undergone TFB for occlusive disease from 2009 to 2019. A descriptive analysis was performed to provide the rates of survival, patency, major complications, and freedom from major amputation in the perioperative period and at 1 year of follow-up. Major complications were compared by procedure indication, with categorical variables analyzed using χ2 tests and continuous variables using analysis of variance. Kaplan-Meier curve analysis was used to estimate survival at the 1- and 5-year follow-up intervals and freedom from major amputation at 1 year. RESULTS: A total of 154 TFB procedures were identified. Of the 154 patients, 59 (38.3%) had undergone previous inflow bypass and 22 (14.2%) had undergone previous leg bypass. The procedure indications included claudication (n = 66; 42.9%), rest pain (n = 59; 38.3%), tissue loss (n = 19; 12.3%), and acute limb ischemia (n = 10; 6.5%). Major complications (eg, wound infection, respiratory, major stroke, new dialysis, cardiac, embolic, major amputation, occlusion) occurred in 31.2% of the cohort. When examined by indication, the acute limb ischemia and claudication cohorts had an increased rate of major complications (acute limb ischemia, 60.0%; claudication, 34.8%; critical limb ischemia, 24.4%; P = .05). The survival rate at 30 days was 95.5%, with a Kaplan-Meier estimated 1-year survival rate of 92.7% ± 2.2%. Primary patency at discharge from the index hospitalization was 92.9% and 89.0% at 1 year. Postoperative major amputation was required for 1 patient during the index hospitalization, for a Kaplan-Meier estimated freedom from major amputation at 1 year of 97.1% ± 2.2%. Two patients developed in-hospital bypass occlusion and three patients developed occlusion within 1 year, for an overall freedom from occlusion rate of 96.8% at 1 year. CONCLUSIONS: TFB is associated with a high rate of perioperative major complications; however, the long-term survival and patency after TFB remained acceptable when performed for limb salvage. The high perioperative complication rates of TFB procedures performed for claudication suggest TFB should be used rarely in this population. These data can be used to counsel patients and aid in decision making before operative intervention.

The association between preoperative length of stay and surgical site infection after lower extremity bypass for chronic limb-threatening ischemia.

OBJECTIVE: Surgical site infection (SSI) is an important complication of lower extremity bypass (LEB) and the rate of SSI after LEB varies widely in the existing literature, ranging from 4% to 31%. Prolonged length of stay (LOS) has been implicated in the occurrence of SSI across multiple surgical disciplines. The impact of preoperative LOS in patients with chronic limb-threatening ischemia (CLTI) undergoing LEB is unknown. We examined the association of preoperative LOS on SSI after LEB. METHODS: A retrospective analysis of the Society for Vascular Surgery Vascular Quality Initiative Infrainguinal Bypass Registry identified patients undergoing elective LEB for chronic limb-threatening ischemia from 2003 to 2019. Patients undergoing LEB for acute limb ischemia, urgent/emergent procedures, aneurysm, or who had concomitant suprainguinal bypass were excluded. The primary outcome measure was postoperative SSI. Multivariable forward stepwise logistic regression was then performed including all variables with a P value of less than .10 in both matched and unmatched cohorts to evaluate for demographic and perioperative predictors of SSI. Propensity score matching was used to create matched cohorts of patients for each LOS group. RESULTS: A total of 17,883 LEB procedures were selected for inclusion: 0 days (12,362 LEB), 1 to 2 days (1737 LEB), and 3 to 14 days (3784 LEB). Patients with the greatest preoperative LOS were more likely to have vein mapping (0 days preoperative LOS, 66.3%; 1-2 days, 65.2%; 3-14 days, 73.2%; P < .01) or computed tomography angiography/magnetic resonance angiography (0 days, 32.1%; 1-2 days, 34.4%; 3-14 days, 38.4%; P < .01). Patients with 3 or more days of preoperative LOS had longer procedure lengths (0 days, 244 minutes; 1-2 days, 243 minutes; 3-14 days, 255 minutes; P < .01) and were more likely to have completion angiogram (0 days, 27.1%; 1-2 days, 29.5%; 3-14 days, 31.6%; P = .02). Multivariable logistic regression demonstrated that preoperative LOS of 3 to 14 days was associated with increased rate of SSI (odds ratio [OR], 1.92; 95% confidence interval [CI], 1.20-3.07; P = .01). Transfusion of 3 or more units (OR, 2.87; 95% CI, 1.89-4.36; P < .01) and prolonged procedure length (>220 minutes; OR, 1.86; 95% CI, 1.26-2.73; P < .01) were also significantly associated with postoperative SSIs. CONCLUSIONS: Many factors including preoperative comorbidities and operative complexity covary with preoperative LOS as risk factors for SSI. However, when patients are matched based on comorbidities and factors that would predict overall clinical complexity, preoperative LOS remains important in predicting SSI.

Carotid endarterectomy with concomitant distal endovascular intervention is associated with increased rates of stroke and death.

OBJECTIVE: Carotid endarterectomy (CEA) with concomitant distal endovascular intervention (CEA+D) is infrequently necessary but has often been used as a salvage maneuver when complications occur during CEA. The present study aimed to determine whether preoperative risk factors associated with CEA requiring CEA+D exist and to evaluate the outcomes compared with isolated CEA. METHODS: The Vascular Quality Initiative CEA registry was used to identify patients who had undergone CEA or CEA+D for asymptomatic or symptomatic carotid stenosis from 2013 to 2019. Data regarding distal intervention included whether angioplasty or stenting of the distal internal carotid artery (ICA) and/or bifurcation had been required. However, information regarding the indication or whether the intervention had been planned was not included. The χ2 test and analysis of variance were used to evaluate the categorical and continuous perioperative variables. Variables with P < .20 on univariate analysis were included in the multivariable analysis to assess for preoperative predictors of the need for CEA+D and the association with perioperative stroke. RESULTS: From 2013 to 2019, 327 CEA+D cases were identified and compared with 105,192 isolated CEA cases. The CEA+D patients were more likely to have undergone previous ipsilateral CEA (CEA, 1.8%; CEA+D, 4.9%; P < .01) and contralateral ICA occlusion (CEA, 4.6%; CEA+D, 11.0%; P < .01) but were less likely to have had ipsilateral stenosis ≥70% (CEA, 88.3%; CEA+D, 80.6%; P < .01). The preoperative factors associated with the need for CEA+D on multivariable analysis included previous peripheral vascular intervention, American Society of Anesthesiologists class ≥4, contralateral ICA occlusion, low-volume surgeon, and previous ipsilateral CEA. CEA+D was associated with significantly increased rates of stroke in both asymptomatic (CEA+D, 3.9%; CEA, 0.9%; P < .01) and symptomatic (CEA+D, 9.4%; CEA, 1.9%; P < .01) patients. CEA+D was associated with decreased rates of 30-day survival in both asymptomatic (CEA+D, 98.3%; CEA, 99.4%; P = .02) and symptomatic (CEA+D, 94.8%; CEA, 99.1%; P < .01) cohorts. On multivariable analysis, CEA+D remained significantly associated with stroke (odds ratio, 3.17; 95% confidence interval, 1.80-5.60; P < .01). Other factors significantly associated with perioperative stroke included procedure length >135 minutes, diabetes, hypertension, shunt for indication, symptomatic status, previous ipsilateral CEA, contralateral ICA occlusion, urgent or emergent procedure, intravenous medications for hemodynamic instability, and re-exploration at the initial operation. CONCLUSIONS: Although markers of more significant cardiovascular disease burden were associated with the use of CEA+D, their power to predict CEA+D use was limited. In cases in which CEA+D was used, CEA+D was associated with significantly greater rates of perioperative stroke and mortality compared with isolated CEA for both asymptomatic and symptomatic patients, which could be useful for framing the expected outcomes after these procedures.

Examination of race and infrainguinal bypass conduit use in the Society for Vascular Surgery Vascular Quality Initiative.

BACKGROUND: Vein conduit is known to have better patency than prosthetic for infrainguinal bypass. Here we explore if racial disparities exist in infrainguinal bypass vein conduit use amid preoperative patient and systemic factors. METHODS: Retrospective Society for Vascular Surgery Vascular Quality Initiative data for 23,959 infrainguinal bypasses between 2003 and 2017 for occlusive disease were analyzed. For homogeneity, only infrainguinal bypasses originating from the common femoral artery were included. Demographics of patients receiving vein vs prosthetic were compared and logistic regression analyses were performed with race and preoperative factors to evaluate for predictors of vein conduit use. RESULTS: Adjusted regression models demonstrated black patients were 76% as likely (p < .001) and Hispanic patients 79% as likely (p = .003) to have vein conduit compared to white patients. Factors positively correlating with vein use included vein mapping, more distal bypass target, tissue loss or acute ischemia bypass indications, commercial insurance, and weight. Factors against vein use included advanced age, female gender, ASA class 4, urgent procedure, preoperative mobility limitation, prior CABG or leg bypass, prior smoking, preoperative anticoagulation, and a bypass performed in the Southern US or before 2012. While black and Hispanic patients were less likely to receive vein, they were vein mapped at similar or higher rates than other groups. CONCLUSION: Racial disparities exist in conduit use for infrainguinal bypass, with black and Hispanic patients less likely to receive vein bypasses. However, the contribution of race to conduit selection is small in adjusted and unadjusted models. Overall, pre-operative variables in the Vascular Quality Initiative poorly predicted vein conduit use for infrainguinal bypass.

LSO:Ce Inorganic Scintillators Are Biocompatible With Neuronal and Circuit Function.

Optogenetics is widely used in neuroscience to control neural circuits. However, non-invasive methods for light delivery in brain are needed to avoid physical damage caused by current methods. One potential strategy could employ x-ray activation of radioluminescent particles (RPLs), enabling localized light generation within the brain. RPLs composed of inorganic scintillators can emit light at various wavelengths depending upon composition. Cerium doped lutetium oxyorthosilicate (LSO:Ce), an inorganic scintillator that emits blue light in response to x-ray or ultraviolet (UV) stimulation, could potentially be used to control neural circuits through activation of channelrhodopsin-2 (ChR2), a light-gated cation channel. Whether inorganic scintillators themselves negatively impact neuronal processes and synaptic function is unknown, and was investigated here using cellular, molecular, and electrophysiological approaches. As proof of principle, we applied UV stimulation to 4 µm LSO:Ce particles during whole-cell recording of CA1 pyramidal cells in acute hippocampal slices from mice that expressed ChR2 in glutamatergic neurons. We observed an increase in frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs), indicating activation of ChR2 and excitation of neurons. Importantly, LSO:Ce particles did not affect survival of primary mouse cortical neurons, even after 24 h of exposure. In extracellular dendritic field potential recordings, no change in the strength of basal glutamatergic transmission was observed during exposure to LSO:Ce microparticles. However, the amplitude of the fiber volley was slightly reduced with high stimulation. Additionally, there was a slight decrease in the frequency of sEPSCs in whole-cell voltage-clamp recordings from CA1 pyramidal cells, with no change in current amplitudes. The amplitude and frequency of spontaneous inhibitory postsynaptic currents were unchanged. Finally, long term potentiation (LTP), a synaptic modification believed to underlie learning and memory and a robust measure of synaptic integrity, was successfully induced, although the magnitude was slightly reduced. Together, these results show LSO:Ce particles are biocompatible even though there are modest effects on baseline synaptic function and long-term synaptic plasticity. Importantly, we show that light emitted from LSO:Ce particles is able to activate ChR2 and modify synaptic function. Therefore, LSO:Ce inorganic scintillators are potentially viable for use as a new light delivery system for optogenetics.

High Density, Double-Sided, Flexible Optoelectronic Neural Probes With Embedded µLEDs.

Optical stimulation and imaging of neurons deep in the brain require implantable optical neural probes. External optical access to deeper regions of the brain is limited by scattering and absorption of light as it propagates through tissue. Implantable optoelectronic probes capable of high-resolution light delivery and high-density neural recording are needed for closed-loop manipulation of neural circuits. Micro-light-emitting diodes (µLEDs) have been used for optical stimulation, but predominantly on rigid silicon or sapphire substrates. Flexible polymer neural probes would be preferable for chronic applications since they cause less damage to brain tissue. Flexible µLED neural probes have been recently implemented by flip-chip bonding of commercially available µLED chips onto flexible substrates. Here, we demonstrate a monolithic design for flexible optoelectronic neural interfaces with embedded gallium nitride µLEDs that can be microfabricated at wafer-scale. Parylene C is used as the substrate and insulator due to its biocompatibility, compliance, and optical transparency. We demonstrate one-dimensional and two-dimensional individually-addressable µLED arrays. Our µLEDs have sizes as small as 22 × 22 µm in arrays of up to 32 µLEDs per probe shank. These devices emit blue light at a wavelength of 445 nm, suitable for stimulation of channelrhodopsin-2, with output powers greater than 200 µW at 2 mA. Our flexible optoelectronic probes are double-sided and can illuminate brain tissue from both sides. Recording electrodes are co-fabricated with µLEDs on the front- and backside of the optoelectronic probes for electrophysiology recording of neuronal activity from the volumes of tissue on the front- and backside simultaneously with bi-directional optical stimulation.

Cyclic O3 exposure synergizes with aging leading to memory impairment in male APOE ε3, but not APOE ε4, targeted replacement mice.

The etiology of late-onset Alzheimer's disease is unknown. Recent epidemiological studies suggest that exposure to high levels of ozone (O3) may be a risk factor for late-onset Alzheimer's disease. Nonetheless, whether and how O3 exposure contributes to AD development remains to be determined. In this study, we tested the hypothesis that O3 exposure synergizes with the genetic risk factor APOE ε4 and aging leading to AD, using male apolipoprotein E (apoE)4 and apoE3 targeted replacement mice as men have increased risk exposure to high levels of O3 via working environments and few studies have addressed APOE ε4 effects on males. Surprisingly, our results show that O3 exposure impairs memory in old apoE3, but not old apoE4 or young apoE3 and apoE4, male mice. Further studies show that old apoE4 mice have increased hippocampal activities or expression of some enzymes involved in antioxidant defense, diminished protein oxidative modification, and neuroinflammation following O3 exposure compared with old apoE3 mice. These novel findings highlight the complexity of interactions between APOE genotype, age, and environmental exposure in AD development.

Rapid Plasticity of Higher-Order Thalamocortical Inputs during Sensory Learning.

Neocortical circuits are sensitive to experience, showing both anatomical and electrophysiological changes in response to altered sensory input. We examined input- and cell-type-specific changes in thalamo- and intracortical pathways during learning using an automated, home-cage sensory association training (SAT) paradigm coupling multi-whisker stimulation to a water reward. We found that the posterior medial nucleus (POm) but not the ventral posterior medial (VPM) nucleus of the thalamus drives increased cortical activity after 24 h of SAT, when behavioral evidence of learning first emerges. Synaptic strengthening within the POm thalamocortical pathway was first observed at thalamic inputs to L5 and was not generated by sensory stimulation alone. Synaptic changes in L2 were delayed relative to L5, requiring 48 h of SAT to drive synaptic plasticity at thalamic and intracortical inputs onto L2 Pyr neurons. These data identify the POm thalamocortical circuit as a site of rapid synaptic plasticity during learning and suggest a temporal sequence to learning-evoked synaptic changes in the sensory cortex.

"Stealth dissemination" of macrophage-tumor cell fusions cultured from blood of patients with pancreatic ductal adenocarcinoma.

Here we describe isolation and characterization of macrophage-tumor cell fusions (MTFs) from the blood of pancreatic ductal adenocarcinoma (PDAC) patients. The MTFs were generally aneuploidy, and immunophenotypic characterizations showed that the MTFs express markers characteristic of PDAC and stem cells, as well as M2-polarized macrophages. Single cell RNASeq analyses showed that the MTFs express many transcripts implicated in cancer progression, LINE1 retrotransposons, and very high levels of several long non-coding transcripts involved in metastasis (such as MALAT1). When cultured MTFs were transplanted orthotopically into mouse pancreas, they grew as obvious well-differentiated islands of cells, but they also disseminated widely throughout multiple tissues in "stealth" fashion. They were found distributed throughout multiple organs at 4, 8, or 12 weeks after transplantation (including liver, spleen, lung), occurring as single cells or small groups of cells, without formation of obvious tumors or any apparent progression over the 4 to 12 week period. We suggest that MTFs form continually during PDAC development, and that they disseminate early in cancer progression, forming "niches" at distant sites for subsequent colonization by metastasis-initiating cells.

Acute Increases in Protein O-GlcNAcylation Dampen Epileptiform Activity in Hippocampus.

O-GlcNAcylation is a ubiquitous and dynamic post-translational modification involving the O-linkage of ß-N-acetylglucosamine to serine/threonine residues of membrane, cytosolic, and nuclear proteins. This modification is similar to phosphorylation and regarded as a key regulator of cell survival and homeostasis. Previous studies have shown that phosphorylation of serine residues on synaptic proteins is a major regulator of synaptic strength and long-term plasticity, suggesting that O-GlcNAcylation of synaptic proteins is likely as important as phosphorylation; however, few studies have investigated its role in synaptic efficacy. We recently demonstrated that acutely increasing O-GlcNAcylation induces a novel form of LTD at CA3-CA1 synapses, O-GlcNAc LTD. Here, using hippocampal slices from young adult male rats and mice, we report that epileptiform activity at CA3-CA1 synapses, generated by GABAAR inhibition, is significantly attenuated when protein O-GlcNAcylation is pharmacologically increased. This dampening effect is lost in slices from GluA2 KO mice, indicating a requirement of GluA2-containing AMPARs, similar to expression of O-GlcNAc LTD. Furthermore, we find that increasing O-GlcNAcylation decreases spontaneous CA3 pyramidal cell activity under basal and hyperexcitable conditions. This dampening effect was also observed on cortical hyperexcitability during in vivo EEG recordings in awake mice where the effects of the proconvulsant pentylenetetrazole are attenuated by acutely increasing O-GlcNAcylation. Collectively, these data demonstrate that the post-translational modification, O-GlcNAcylation, is a novel mechanism by which neuronal and synaptic excitability can be regulated, and suggest the possibility that increasing O-GlcNAcylation could be a novel therapeutic target to treat seizure disorders and epilepsy.SIGNIFICANCE STATEMENT We recently reported that an acute pharmacological increase in protein O-GlcNAcylation induces a novel form of long-term synaptic depression at hippocampal CA3-CA1 synapses (O-GlcNAc LTD). This synaptic dampening effect on glutamatergic networks suggests that increasing O-GlcNAcylation will depress pathological hyperexcitability. Using in vitro and in vivo models of epileptiform activity, we show that acutely increasing O-GlcNAc levels can significantly attenuate ongoing epileptiform activity and prophylactically dampen subsequent seizure activity. Together, our findings support the conclusion that protein O-GlcNAcylation is a regulator of neuronal excitability, and it represents a promising target for further research on seizure disorder therapeutics.

High antibiotic resistance of Helicobacter pylori and its effect on tailored and empiric eradication of the organism in Lower Silesia, Poland.

BACKGROUND: At present, the resistance to antibiotics is considered the most important reason for Helicobacter pylori (HP) eradication failure. The aim of this study was to estimate the prevalence of antimicrobial resistance of HP strains and to evaluate tailored and empiric therapeutic regimens in patients with peptic ulcer disease associated with infection of this microorganism. MATERIALS AND METHODS: Between May 2011 and February 2013, 185 consecutive Polish patients with at least one positive Helicobacter pylori test (urease test, histopathologic examination, and/or culture) underwent eradication therapy. Those with positive culture were prescribed a tailored triple regimen, whereas those with no culture available received an empiric quadruple concomitant regimen or levofloxacin-containing triple therapy. RESULTS: There were no HP strains resistant to amoxicillin; however, 56.7% were resistant to metronidazole, 55.2% to clarithromycin, and 5.9% to levofloxacin. Dual resistance was detected in 32.8% of individuals. Tailored and empiric therapies achieve cure rates, respectively, 95.5% and 86.6% by intention-to-treat and 95.5% and 91.3% by per-protocol analysis (P > 0.05). CONCLUSIONS: Antibiotic resistance is notably high in Poland currently, but both tailored and empiric therapies can achieve acceptable cure rates equal to or higher than 90%.

Why Does Exercise "Trigger" Adaptive Protective Responses in the Heart?

Numerous epidemiological studies suggest that individuals who exercise have decreased cardiac morbidity and mortality. Pre-clinical studies in animal models also find clear cardioprotective phenotypes in animals that exercise, specifically characterized by lower myocardial infarction and arrhythmia. Despite the clear benefits, the underlying cellular and molecular mechanisms that are responsible for exercise preconditioning are not fully understood. In particular, the adaptive signaling events that occur during exercise to "trigger" cardioprotection represent emerging paradigms. In this review, we discuss recent studies that have identified several different factors that appear to initiate exercise preconditioning. We summarize the evidence for and against specific cellular factors in triggering exercise adaptations and identify areas for future study.

Interaction of metabolic stress with chronic mild stress in altering brain cytokines and sucrose preference.

There is growing evidence that metabolic stressors increase an organism's risk of depression. Chronic mild stress is a popular animal model of depression and several serendipitous findings have suggested that food deprivation prior to sucrose testing in this model is necessary to observe anhedonic behaviors. Here, we directly tested this hypothesis by exposing animals to chronic mild stress and used an overnight 2-bottle sucrose test (food ad libitum) on Day 5 and 10, then food and water deprive animals overnight and tested their sucrose consumption and preference in a 1-hr sucrose test the following morning. Approximately 65% of stressed animals consumed sucrose and showed a sucrose preference similar to nonstressed controls in an overnight sucrose test, and 35% showed a decrease in sucrose intake and preference. Following overnight food and water deprivation the previously "resilient" animals showed a significant decrease in sucrose preference and greatly reduced sucrose intake. In addition, we evaluated whether the onset of anhedonia following food and water deprivation corresponds to alterations in corticosterone, epinephrine, circulating glucose, or interleukin-1 beta (IL-1ß) expression in limbic brain areas. Although all stressed animals showed adrenal hypertrophy and elevated circulating epinephrine, only stressed animals that were food deprived were hypoglycemic compared with food-deprived controls. Additionally, food and water deprivation significantly increased hippocampus IL-1ß while food and water deprivation only increased hypothalamus IL-1ß in stress-susceptible animals. These data demonstrate that metabolic stress of food and water deprivation interacts with chronic stressor exposure to induce physiological and anhedonic responses.

Cell adhesion proteins and the pathogenesis of autism spectrum disorders.

Current theories on the pathogenesis of autism spectrum disorders (ASD) maintain that the associated cognitive and behavioral symptoms are caused by aberrant synaptic transmission affecting specific brain circuits. Transgenic mouse models have implicated the involvement of cell adhesion proteins in synaptic dysfunction and ASD pathogenesis. Recently, Aoto et al. (Cell 154: 75-88, 2013) has shown that alternatively spliced neurexin proteins affect the efficacy of AMPA receptor-mediated excitatory currents in both cultured neuronal networks and acute hippocampal slices constituting a potential ASD-related electrophysiological phenotype.

1x11 few-mode fiber wavelength selective switch using photonic lanterns.

We demonstrate an 11 port count wavelength selective switch (WSS) supporting spatial superchannels of three spatial modes, based on the combination of photonic lanterns and a high-port count single-mode WSS.

Beginning robotic assisted colorectal surgery - it's harder than it looks!

INTRODUCTION: Laparoscopy has been introduced into the field of colorectal surgery with the aim of reducing morbidity. One of the major barriers to overcome is the steep learning curve. Robotic surgery offers substantial advantages over traditional laparoscopy, which make the whole procedure more user friendly. AIM: To present our initial experiences with robotic assisted colorectal surgery. MATERIAL AND METHODS: Thirty-five patients with colorectal cancer underwent robotic assisted procedures between 2011 and 2013. RESULTS: In total we performed 16 low anterior resections, 14 right colectomies, 3 abdominosacral resections and 2 left colectomies. There were 22 males and 13 females. The mean operative time was 315 ±65 min for a low anterior resection. The mean length of hospital stay was 6.4 ±1 days. There were 4 conversions to open procedures, 2 anastomotic leaks, and 1 colovaginal fistula. The mean lymph node yield was 12.7 ±4.3. The resection margin was negative in all but 1 patient. CONCLUSIONS: We agree with the opinion that robotic surgery brings many advantages in pelvic dissections. In order to facilitate safe acquisition of robotic total mesorectal excision skills, surgeons should begin with female patients, and less advanced rectal cancer. In some instances robotic assistance can be helpful in right colectomies.

Reduction of early reperfusion injury with the mitochondria-targeting peptide bendavia.

We recently showed that Bendavia, a novel mitochondria-targeting peptide, reduced infarction and no-reflow across several experimental models. The purpose of this study was to determine the therapeutic timing and mechanism of action that underlie Bendavia's cytoprotective property. In rabbits exposed to in vivo ischemia/reperfusion (30/180 min), Bendavia administered 20 minutes prior to reperfusion (0.05 mg/kg/h, intravenously) reduced myocardial infarct size by ∼50% when administered for either 1 or 3 hours of reperfusion. However, when Bendavia perfusion began just 10 minutes after the onset of reperfusion, the protection against infarction and no-reflow was completely lost, indicating that the mechanism of protection is occurring early in reperfusion. Experiments in isolated mouse liver mitochondria found no discernible effect of Bendavia on blocking the permeability transition pore, and studies in isolated heart mitochondria showed no effect of Bendavia on respiratory rates. As Bendavia significantly lowered reactive oxygen species (ROS) levels in isolated heart mitochondria, the ROS-scavenging capacity of Bendavia was compared to well-known ROS scavengers using in vitro (cell-free) systems that enzymatically generate ROS. Across doses ranging from 1 nmol/L to 1 mmol/L, Bendavia showed no discernible ROS-scavenging properties, clearly differentiating itself from prototypical scavengers. In conclusion, Bendavia is a promising candidate to reduce cardiac injury when present at the onset of reperfusion but not after reperfusion has already commenced. Given that both infarction and no-reflow are related to increased cellular ROS, Bendavia's protective mechanism of action likely involves reduced ROS generation (as opposed to augmented scavenging) by endothelial and myocyte mitochondria.

Stage of the estrous cycle does not influence myocardial ischemia-reperfusion injury in rats (Rattus norvegicus).

Even though cardiovascular disease is the leading cause of death for men and women, the vast majority of animal studies use male animals. Because female reproductive hormones have been associated with cardioprotective states, many investigators avoid using female animals because these hormones are cyclical and may introduce experimental variability. In addition, no studies have investigated the specific effects of the estrous cycle on cardiac ischemic injury. This study was conducted to determine whether the estrous cycle stage influences the susceptibility to ischemic injury in rat hearts. Estrous cycle stage was determined by using vaginal smear cytology, after which hearts underwent either in vivo (surgical) or ex vivo (isolated) ischemia-reperfusion injury. For in vivo studies, the left anterior coronary artery was ligated for 25 min of ischemia and subsequently released for 120 min of reperfusion. Infarct sizes were 42% ± 6%; 49% ± 4%; 40% ± 9%; 47% ± 9% of the zone-at-risk for rats in proestrus, estrus, metestrus, and diestrus, respectively. For ex vivo studies, isolated, perfused hearts underwent global ischemia and reperfusion for 25 and 120 min, respectively. Similar to our in vivo studies, the ex vivo rat model showed no significant differences in susceptibility to infarction or extent of cardiac arrhythmia according to estrous stage. To our knowledge, these studies provide the first direct evidence that the stage of estrous cycle does not significantly alter cardiac ischemia-reperfusion injury in rats.

Redox-dependent increases in glutathione reductase and exercise preconditioning: role of NADPH oxidase and mitochondria.

AIMS: We have previously shown that exercise leads to sustainable cardioprotection through a mechanism involving improved glutathione replenishment. This study was conducted to determine if redox-dependent modifications in glutathione reductase (GR) were involved in exercise cardioprotection. Furthermore, we sought to determine if reactive oxygen species generated by NADPH oxidase and/or mitochondria during exercise were triggering events for GR modulations. METHODS AND RESULTS: Rats were exercised for 10 consecutive days, after which isolated hearts were exposed to ischaemia/reperfusion (25 min/120 min). Exercise protected against infarction and arrhythmia, and preserved coronary flow. The GR inhibitor BCNU abolished the beneficial effects. GR activity was increased following exercise in a redox-dependent manner, with no change in GR protein levels. Because fluorescent labelling of GR protein thiols showed lower amounts of reduced thiols after exercise, we sought to determine the source of intracellular reactive oxygen species that may be activating GR. Subsets of animals were exercised immediately after treatment with either NADPH-oxidase inhibitors apocynin or Vas2870, or with mitoTEMPO or Bendavia, which reduce mitochondrial reactive oxygen species levels. The cardioprotective effects of exercise were abolished if animals exercised in the presence of NADPH oxidase inhibitors, in clear contrast to the mitochondrial reagents. These changes correlated with thiol-dependent modifications of GR. CONCLUSION: Adaptive cardioprotective signalling is triggered by reactive oxygen species from NADPH oxidase, and leads to improved glutathione replenishment through redox-dependent modifications in GR.