Optimized workplace risk mitigation measures for SARS-CoV-2 in 2022.

596 million SARS-CoV-2 cases have been reported and over 12 billion vaccine doses have been administered. As vaccination rates increase, a gap in knowledge exists regarding appropriate thresholds for escalation and de-escalation of workplace COVID-19 preventative measures. We conducted 133,056 simulation experiments, evaluating the spread of SARS-CoV-2 virus in hypothesized working environments subject to COVID-19 infections from the community. We tested the rates of workplace-acquired infections based on applied isolation strategies, community infection rates, methods and scales of testing, non-pharmaceutical interventions, variant predominance, vaccination coverages, and vaccination efficacies. When 75% of a workforce is vaccinated with a 70% efficacious vaccine against infection, then no masking or routine testing + isolation strategies are needed to prevent workplace-acquired omicron variant infections when the community infection rate per 100,000 persons is ≤ 1. A CIR ≤ 30, and ≤ 120 would result in no workplace-acquired infections in this same scenario against the delta and alpha variants, respectively. Workforces with 100% worker vaccination can prevent workplace-acquired infections with higher community infection rates. Identifying and isolating workers with antigen-based SARS-CoV-2 testing methods results in the same or fewer workplace-acquired infections than testing with slower turnaround time polymerase chain reaction methods. Risk migration measures such as mask-wearing, testing, and isolation can be relaxed, or escalated, in commensurate with levels of community infections, workforce immunization, and risk tolerance. The interactive heatmap we provide can be used for immediate, parameter-based case count predictions to inform institutional policy making. The simulation approach we have described can be further used for future evaluation of strategies to mitigate COVID-19 spread.

Single-nucleus and spatial transcriptome profiling of pancreatic cancer identifies multicellular dynamics associated with neoadjuvant treatment.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal and treatment-refractory cancer. Molecular stratification in pancreatic cancer remains rudimentary and does not yet inform clinical management or therapeutic development. Here, we construct a high-resolution molecular landscape of the cellular subtypes and spatial communities that compose PDAC using single-nucleus RNA sequencing and whole-transcriptome digital spatial profiling (DSP) of 43 primary PDAC tumor specimens that either received neoadjuvant therapy or were treatment naive. We uncovered recurrent expression programs across malignant cells and fibroblasts, including a newly identified neural-like progenitor malignant cell program that was enriched after chemotherapy and radiotherapy and associated with poor prognosis in independent cohorts. Integrating spatial and cellular profiles revealed three multicellular communities with distinct contributions from malignant, fibroblast and immune subtypes: classical, squamoid-basaloid and treatment enriched. Our refined molecular and cellular taxonomy can provide a framework for stratification in clinical trials and serve as a roadmap for therapeutic targeting of specific cellular phenotypes and multicellular interactions.

Optimized Post-Vaccination Strategies and Preventative Measures for SARS-CoV-2.

Introduction: Since March of 2020, over 210 million SARS-CoV-2 cases have been reported and roughly five billion doses of a SARS-CoV-2 vaccine have been delivered. The rise of the more infectious delta variant has recently indicated the value of reinstating previously relaxed non-pharmacological and test-driven preventative measures. These efforts have been met with resistance, due, in part, to a lack of site-specific quantitative evidence which can justify their value. As vaccination rates continue to increase, a gap in knowledge exists regarding appropriate thresholds for escalation and de-escalation of COVID-19 preventative measures. Methods: We conducted a series of simulation experiments, trialing the spread of SARS-CoV-2 virus in a hypothesized working environment that is subject to COVID-19 infections from the surrounding community. We established cohorts of individuals who would, in simulation, work together for a set period of time. With these cohorts, we tested the rates of workplace and community acquired infections based on applied isolation strategies, community infection rates (CIR), scales of testing, non-pharmaceutical interventions, variant predominance's and testing strategies, vaccination coverages, and vaccination efficacies of the members included. Permuting through each combination of these variables, we estimated expected case counts for 33,462 unique workplace scenarios. Results: When the CIR is 5 new confirmed cases per 100,000 or fewer, and at 50% of the workforce is vaccinated with a 95% efficacious vaccine, then testing daily with an antigen-based or PCR based test in only unvaccinated workers will result in less than one infection through 4,800 person weeks. When the community infection rate per 100,000 persons is less than or equal to 60, and the vaccination coverage of the workforce is 100% with 95% vaccine efficacy then no masking or routine testing + isolation strategies are needed to prevent workplace acquired infections regardless of variant predominance. Identifying and isolating workers with antigen-based SARS-CoV-2 testing methods results in the same or fewer workplace acquired infections than testing with polymerase chain reaction (PCR) methods. Conclusions: Specific scenarios exist in which preventative measures taken to prevent SARS-CoV-2 spread, including masking, and testing plus isolation strategies can safely be relaxed. Further, efficacious testing with quarantine strategies exist for implementation in only unvaccinated cohorts in a workplace. Due to shorter turnaround time, antigen-based testing with lower sensitivity is more effective than PCR testing with higher sensitivities in comparable testing strategies. The general reference interactive heatmap we provide can be used for site specific, immediate, parameter-based case count predictions to inform appropriate institutional policy making.

Pan-Cancer Survival Classification With Clinicopathological and Targeted Gene Expression Features.

Prognostication for patients with cancer is important for clinical planning and management, but remains challenging given the large number of factors that can influence outcomes. As such, there is a need to identify features that can robustly predict patient outcomes. We evaluated 8608 patient tumor samples across 16 cancer types from The Cancer Genome Atlas and generated distinct survival classifiers for each using clinical and histopathological data accessible to standard oncology workflows. For cancers that had poor model performance, we deployed a random-forest-embedded sequential forward selection approach that began with an initial subset of the 15 most predictive clinicopathological features before sequentially appending the next most informative gene as an additional feature. With classifiers derived from clinical and histopathological features alone, we observed cancer-type-dependent model performance and an area under the receiver operating curve (AUROC) range of 0.65 to 0.91 across all 16 cancer types for 1- and 3-year survival prediction, with some classifiers consistently outperforming those for others. As such, for cancers that had poor model performance, we posited that the addition of more complex biomolecular features could enhance our ability to prognose patients where clinicopathological features were insufficient. With the inclusion of gene expression data, model performance for 3 select cancers (glioblastoma, stomach/gastric adenocarcinoma, ovarian serous carcinoma) markedly increased from initial AUROC scores of 0.66, 0.69, and 0.67 to 0.76, 0.77, and 0.77, respectively. As a whole, this study provides a thorough examination of the relative contributions of clinical, pathological, and gene expression data in predicting overall survival and reveals cancer types for which clinical features are already strong predictors and those where additional biomolecular information is needed.

Reducing COVID-19 quarantine with SARS-CoV-2 testing: a simulation study.

OBJECTIVE: To evaluate the effectiveness of SARS-CoV-2 testing on shortening the duration of quarantines for COVID-19 and to identify the most effective choices of testing schedules. DESIGN: We performed extensive simulations to evaluate the performance of quarantine strategies when one or more SARS-CoV-2 tests were administered during the quarantine. Simulations were based on statistical models for the transmissibility and viral loads of SARS-CoV-2 infections and the sensitivities of available testing methods. Sensitivity analyses were performed to evaluate the impact of perturbations in model assumptions on the outcomes of optimal strategies. RESULTS: We found that SARS-CoV-2 testing can effectively reduce the length of a quarantine without compromising safety. A single reverse transcription-PCR (RT-PCR) test performed before the end of quarantine can reduce quarantine duration to 10 days. Two tests can reduce the duration to 8 days, and three highly sensitive RT-PCR tests can justify a 6-day quarantine. More strategic testing schedules and longer quarantines are needed if tests are administered with less-sensitive RT-PCR tests or antigen tests. Shorter quarantines can be used for applications that tolerate a residual postquarantine transmission risk comparable to a 10-day quarantine. CONCLUSIONS: Testing could substantially reduce the length of isolation, reducing the physical and mental stress caused by lengthy quarantines. With increasing capacity and lowered costs of SARS-CoV-2 tests, test-assisted quarantines could be safer and more cost-effective than 14-day quarantines and warrant more widespread use.

Optimal test-assisted quarantine strategies for COVID-19.

OBJECTIVE: To evaluate the effectiveness of SARS-CoV-2 testing on shortening the duration of quarantines for COVID-19 and to identify the most effective choices of testing schedules. DESIGN: We performed extensive simulations to evaluate the performance of quarantine strategies when one or more SARS-CoV-2 tests were administered during the quarantine. Simulations were based on statistical models for the transmissibility and viral loads of SARS-CoV-2 infections and the sensitivities of available testing methods. Sensitivity analyses were performed to evaluate the impact of perturbations in model assumptions on the outcomes of optimal strategies. RESULTS: We found that SARS-CoV-2 testing can effectively reduce the length of a quarantine without compromising safety. A single RT-PCR test performed before the end of quarantine can reduce quarantine duration to 10 days. Two tests can reduce the duration to 8 days, and three highly sensitive RT-PCR tests can justify a 6-day quarantine. More strategic testing schedules and longer quarantines are needed if tests are administered with less sensitive RT-PCR tests or antigen tests. Shorter quarantines can be utilized for applications that tolerate a residual post-quarantine transmission risk comparable to a 10-day quarantine. CONCLUSIONS: Testing could substantially reduce the length of isolation, reducing the physical and mental stress caused by lengthy quarantines. With increasing capacity and lowered costs of SARS-CoV-2 tests, test-assisted quarantines could be safer and more cost-effective than 14-day quarantines and warrant more widespread use. RESEARCH IN CONTEXT: What is already known on this topic?: Recommendations for quarantining individuals who could have been infected with COVID-19 are based on limited evidence.Despite recent theoretical and case studies of test-assisted quarantines, there has been no substantive investigation to quantify the safety and efficacy of, nor an exhaustive search for, optimal test-assisted quarantine strategies. WHAT THIS STUDY ADDS: Our simulations indicate that the 14-day quarantine approach is overly conservative and can be safely shortened if testing is performed.Our recommendations include testing schedules that could be immediately adopted and implemented as government and industry policies. ROLE OF THE FUNDING SOURCE: A major technology company asked that we perform simulations to understand the optimal strategy for managing personnel quarantining before forming cohorts of individuals who would work closely together. The funding entity did not influence the scope or output of the study but requested that we include antigen testing as a component of the quarantining process. Patrick Yu and Peter Matos are employees of Corporate Medical Advisors, and International S.O.S employs Julie McCashin. Other funding sources are research grants and did not influence the investigation.

A Non-covalent Ligand Reveals Biased Agonism of the TRPA1 Ion Channel.

The TRPA1 ion channel is activated by electrophilic compounds through the covalent modification of intracellular cysteine residues. How non-covalent agonists activate the channel and whether covalent and non-covalent agonists elicit the same physiological responses are not understood. Here, we report the discovery of a non-covalent agonist, GNE551, and determine a cryo-EM structure of the TRPA1-GNE551 complex, revealing a distinct binding pocket and ligand-interaction mechanism. Unlike the covalent agonist allyl isothiocyanate, which elicits channel desensitization, tachyphylaxis, and transient pain, GNE551 activates TRPA1 into a distinct conducting state without desensitization and induces persistent pain. Furthermore, GNE551-evoked pain is relatively insensitive to antagonist treatment. Thus, we demonstrate the biased agonism of TRPA1, a finding that has important implications for the discovery of effective drugs tailored to different disease etiologies.

Sulindac plus a phospholipid is effective for polyp reduction and safer than sulindac alone in a mouse model of colorectal cancer development.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and sulindac are effective for colorectal cancer prevention in humans and some animal models, but concerns over gastro-intestinal (GI) ulceration and bleeding limit their potential for chemopreventive use in broader populations. Recently, the combination of aspirin with a phospholipid, packaged as PL-ASA, was shown to reduce GI toxicity in a small clinical trial. However, these studies were done for relatively short periods of time. Since prolonged, regular use is needed for chemopreventive benefit, it is important to know whether GI safety is maintained over longer use periods and whether cancer prevention efficacy is preserved when an NSAID is combined with a phospholipid. METHODS: As a first step to answering these questions, we treated seven to eight-week-old, male and female C57B/6 Apcmin/+ mice with the NSAID sulindac, with and without phosphatidylcholine (PC) for 3-weeks. At the end of the treatment period, we evaluated polyp burden, gastric toxicity, urinary prostaglandins (as a marker of sulindac target engagement), and blood chemistries. RESULTS: Both sulindac and sulindac-PC treatments resulted in significantly reduced polyp burden, and decreased urinary prostaglandins, but sulindac-PC treatment also resulted in the reduction of gastric lesions compared to sulindac alone. CONCLUSIONS: Together these data provide pre-clinical support for combining NSAIDs with a phospholipid, such as phosphatidylcholine to reduce GI toxicity while maintaining chemopreventive efficacy.

The hERG channel activator, RPR260243, enhances protective IKr current early in the refractory period reducing arrhythmogenicity in zebrafish hearts.

Human ether-à-go-go related gene (hERG) K+ channels are important in cardiac repolarization, and their dysfunction causes prolongation of the ventricular action potential, long QT syndrome, and arrhythmia. As such, approaches to augment hERG channel function, such as activator compounds, have been of significant interest due to their marked therapeutic potential. Activator compounds that hinder channel inactivation abbreviate action potential duration (APD) but carry risk of overcorrection leading to short QT syndrome. Enhanced risk by overcorrection of the APD may be tempered by activator-induced increased refractoriness; however, investigation of the cumulative effect of hERG activator compounds on the balance of these effects in whole organ systems is lacking. Here, we have investigated the antiarrhythmic capability of a hERG activator, RPR260243, which primarily augments channel function by slowing deactivation kinetics in ex vivo zebrafish whole hearts. We show that RPR260243 abbreviates the ventricular APD, reduces triangulation, and steepens the slope of the electrical restitution curve. In addition, RPR260243 increases the post-repolarization refractory period. We provide evidence that this latter effect arises from RPR260243-induced enhancement of hERG channel-protective currents flowing early in the refractory period. Finally, the cumulative effect of RPR260243 on arrhythmogenicity in whole organ zebrafish hearts is demonstrated by the restoration of normal rhythm in hearts presenting dofetilide-induced arrhythmia. These findings in a whole organ model demonstrate the antiarrhythmic benefit of hERG activator compounds that modify both APD and refractoriness. Furthermore, our results demonstrate that targeted slowing of hERG channel deactivation and enhancement of protective currents may provide an effective antiarrhythmic approach.NEW & NOTEWORTHY hERG channel dysfunction causes long QT syndrome and arrhythmia. Activator compounds have been of significant interest due to their therapeutic potential. We used the whole organ zebrafish heart model to demonstrate the antiarrhythmic benefit of the hERG activator, RPR260243. The activator abbreviated APD and increased refractoriness, the combined effect of which rescued induced ventricular arrhythmia. Our findings show that the targeted slowing of hERG channel deactivation and enhancement of protective currents caused by the RPR260243 activator may provide an effective antiarrhythmic approach.

Modulation of hERG K+ Channel Deactivation by Voltage Sensor Relaxation.

The hERG (human-ether-à-go-go-related gene) channel underlies the rapid delayed rectifier current, Ikr, in the heart, which is essential for normal cardiac electrical activity and rhythm. Slow deactivation is one of the hallmark features of the unusual gating characteristics of hERG channels, and plays a crucial role in providing a robust current that aids repolarization of the cardiac action potential. As such, there is significant interest in elucidating the underlying mechanistic determinants of slow hERG channel deactivation. Recent work has shown that the hERG channel S4 voltage sensor is stabilized following activation in a process termed relaxation. Voltage sensor relaxation results in energetic separation of the activation and deactivation pathways, producing a hysteresis, which modulates the kinetics of deactivation gating. Despite widespread observation of relaxation behaviour in other voltage-gated K+ channels, such as Shaker, Kv1.2 and Kv3.1, as well as the voltage-sensing phosphatase Ci-VSP, the relationship between stabilization of the activated voltage sensor by the open pore and voltage sensor relaxation in the control of deactivation has only recently begun to be explored. In this review, we discuss present knowledge and questions raised related to the voltage sensor relaxation mechanism in hERG channels and compare structure-function aspects of relaxation with those observed in related ion channels. We focus discussion, in particular, on the mechanism of coupling between voltage sensor relaxation and deactivation gating to highlight the insight that these studies provide into the control of hERG channel deactivation gating during their physiological functioning.

Angiosarcoma of the abdominal aorta after endovascular aneurysm repair.

Primary aortic sarcoma is a rare diagnosis that carries a poor prognosis. This case report features a 68-year-old man, treated 4 years earlier with an endovascular aortic aneurysm repair, who presented with fever, low back discomfort, and abdominal pain. Given the concern for an infected endograft, the patient underwent explantation and replacement with a cadaveric aortoiliac cryograft. Ultimately, the pathology returned as an angiosarcoma. Although endovascular aortic aneurysm repair is the gold standard for abdominal aortic aneurysm repair in patients with suitable anatomy, there are trade-offs associated with less invasive approaches compared with open approaches.

Extracellular protons accelerate hERG channel deactivation by destabilizing voltage sensor relaxation.

hERG channels underlie the delayed-rectifier K+ channel current (IKr), which is crucial for membrane repolarization and therefore termination of the cardiac action potential. hERG channels display unusually slow deactivation gating, which contributes to a resurgent current upon repolarization and may protect against post-depolarization-induced arrhythmias. hERG channels also exhibit robust mode shift behavior, which reflects the energetic separation of activation and deactivation pathways due to voltage sensor relaxation into a stable activated state. The mechanism of relaxation is unknown and likely contributes to slow hERG channel deactivation. Here, we use extracellular acidification to probe the structural determinants of voltage sensor relaxation and its influence on the deactivation gating pathway. Using gating current recordings and voltage clamp fluorimetry measurements of voltage sensor domain dynamics, we show that voltage sensor relaxation is destabilized at pH 6.5, causing an ∼20-mV shift in the voltage dependence of deactivation. We show that the pH dependence of the resultant loss of mode shift behavior is similar to that of the deactivation kinetics acceleration, suggesting that voltage sensor relaxation correlates with slower pore gate closure. Neutralization of D509 in S3 also destabilizes the relaxed state of the voltage sensor, mimicking the effect of protons, suggesting that acidic residues on S3, which act as countercharges to S4 basic residues, are involved in stabilizing the relaxed state and slowing deactivation kinetics. Our findings identify the mechanistic determinants of voltage sensor relaxation and define the long-sought mechanism by which protons accelerate hERG deactivation.

Stabilization of the Activated hERG Channel Voltage Sensor by Depolarization Involves the S4-S5 Linker.

Slow deactivation of hERG channels is critical for preventing cardiac arrhythmia yet the mechanistic basis for the slow gating transition is unclear. Here, we characterized the temporal sequence of events leading to voltage sensor stabilization upon membrane depolarization. Progressive increase in step depolarization duration slowed voltage-sensor return in a biphasic manner (τfast = 34 ms, τslow = 2.5 s). The faster phase of voltage-sensor return slowing correlated with the kinetics of pore opening. The slower component occurred over durations that exceeded channel activation and was consistent with voltage sensor relaxation. The S4-S5 linker mutation, G546L, impeded the faster phase of voltage sensor stabilization without attenuating the slower phase, suggesting that the S4-S5 linker is important for communications between the pore gate and the voltage sensor during deactivation. These data also demonstrate that the mechanisms of pore gate-opening-induced and relaxation-induced voltage-sensor stabilization are separable. Deletion of the distal N-terminus (Δ2-135) accelerated off-gating current, but did not influence the relative contribution of either mechanism of stabilization of the voltage sensor. Lastly, we characterized mode-shift behavior in hERG channels, which results from stabilization of activated channel states. The apparent mode-shift depended greatly on recording conditions. By measuring slow activation and deactivation at steady state we found the "true" mode-shift to be ∼15 mV. Interestingly, the "true" mode-shift of gating currents was ∼40 mV, much greater than that of the pore gate. This demonstrates that voltage sensor return is less energetically favorable upon repolarization than pore gate closure. We interpret this to indicate that stabilization of the activated voltage sensor limits the return of hERG channels to rest. The data suggest that this stabilization occurs as a result of reconfiguration of the pore gate upon opening by a mechanism that is influenced by the S4-S5 linker, and by a separable voltage-sensor intrinsic relaxation mechanism.

External protons destabilize the activated voltage sensor in hERG channels.

Extracellular acidosis shifts hERG channel activation to more depolarized potentials and accelerates channel deactivation; however, the mechanisms underlying these effects are unclear. External divalent cations, e.g., Ca(2+) and Cd(2+), mimic these effects and coordinate within a metal ion binding pocket composed of three acidic residues in hERG: D456 and D460 in S2 and D509 in S3. A common mechanism may underlie divalent cation and proton effects on hERG gating. Using two-electrode voltage clamp, we show proton sensitivity of hERG channel activation (pKa = 5.6), but not deactivation, was greatly reduced in the presence of Cd(2+) (0.1 mM), suggesting a common binding site for the Cd(2+) and proton effect on activation and separable effects of protons on activation and deactivation. Mutational analysis confirmed that D509 plays a critical role in the pH dependence of activation, as shown previously, and that cooperative actions involving D456 and D460 are also required. Importantly, neutralization of all three acidic residues abolished the proton-induced shift of activation, suggesting that the metal ion binding pocket alone accounts for the effects of protons on hERG channel activation. Voltage-clamp fluorimetry measurements demonstrated that protons shifted the voltage dependence of S4 movement to more depolarized potentials. The data indicate a site and mechanism of action for protons on hERG activation gating; protonation of D456, D460 and D509 disrupts interactions between these residues and S4 gating charges to destabilize the activated configuration of S4.

Single incision laparoscopic right hemicolectomy: different approaches.

BACKGROUND: Single incision laparoscopic colectomy has been performed in recent years, and has been shown to be feasible and safe. This study was to assess the feasibility of single incision laparoscopic right hemicolectomy and to compare the differences in different approaches. METHODS: This retrospective study included eighteen patients with carcinoma of caecum and ascending colon, undergoing single incision laparoscopic right hemicolectomy. This study also compared single incision laparoscopic right hemicolectomy using different approaches: (1) single incision multiport, (2) single access port and (3) glove port. RESULTS: There was no statistical difference in surgical outcomes. Concerning the surgeon's satisfaction toward three methods, overcrowding and durability were similar but the single incision multiport was associated with the highest gas-leak and the "glove" port was associated with poor durability. However, the method of single incision multiport has the lowest average cost of the special trocar or port in each operation. The operative time and blood loss of the operations in this study were comparable to previous publications. CONCLUSION: There was no significant difference between different approaches of single incision laparoscopic right hemicolectomy for colonic cancer in right side colon.

Single incision laparoscopic right hemicolectomy: different approaches / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Single incision laparoscopic colectomy has been performed in recent years, and has been shown to be feasible and safe. This study was to assess the feasibility of single incision laparoscopic right hemicolectomy and to compare the differences in different approaches.</p><p><b>METHODS</b>This retrospective study included eighteen patients with carcinoma of caecum and ascending colon, undergoing single incision laparoscopic right hemicolectomy. This study also compared single incision laparoscopic right hemicolectomy using different approaches: (1) single incision multiport, (2) single access port and (3) glove port.</p><p><b>RESULTS</b>There was no statistical difference in surgical outcomes. Concerning the surgeon's satisfaction toward three methods, overcrowding and durability were similar but the single incision multiport was associated with the highest gas-leak and the "glove" port was associated with poor durability. However, the method of single incision multiport has the lowest average cost of the special trocar or port in each operation. The operative time and blood loss of the operations in this study were comparable to previous publications.</p><p><b>CONCLUSION</b>There was no significant difference between different approaches of single incision laparoscopic right hemicolectomy for colonic cancer in right side colon.</p>

Proton block of the pore underlies the inhibition of hERG cardiac K+ channels during acidosis.

Human ether-a-go-go-related gene (hERG) potassium channels are critical determinants of cardiac repolarization. Loss of function of hERG channels is associated with Long QT Syndrome, arrhythmia, and sudden death. Acidosis occurring as a result of myocardial ischemia inhibits hERG channel function and may cause a predisposition to arrhythmias. Acidic pH inhibits hERG channel maximal conductance and accelerates deactivation, likely by different mechanisms. The mechanism underlying the loss of conductance has not been demonstrated and is the focus of the present study. The data presented demonstrate that, unlike in other voltage-gated potassium (Kv) channels, substitution of individual histidine residues did not abolish the pH dependence of hERG channel conductance. Abolition of inactivation, by the mutation S620T, also did not affect the proton sensitivity of channel conductance. Instead, voltage-dependent channel inhibition (δ = 0.18) indicative of pore block was observed. Consistent with a fast block of the pore, hERG S620T single channel data showed an apparent reduction of the single channel current amplitude at low pH. Furthermore, the effect of protons was relieved by elevating external K(+) or Na(+) and could be modified by charge introduction within the outer pore. Taken together, these data strongly suggest that extracellular protons inhibit hERG maximal conductance by blocking the external channel pore.

Management of thoracic esophageal perforations.

OBJECTIVE: To assess our results of a prospective algorithm applied to patients with thoracic esophageal perforation. METHODS: A retrospective review of a prospective algorithm. Patients with esophageal perforation underwent an esophagram. If there was a contained esophageal perforation they were admitted, kept nothing by mouth, and restudied in 3-5 days. If the leak was not contained, they underwent operative repair. RESULTS: From 1/1998 to 6/2009 there were 81 patients. The gastrograffin swallow showed 56 patients had contained perforations and 25 did not. Twenty-two of the 25 patients with noncontained perforation underwent immediate operative repair (one patient refused surgery, two were not stable enough for the operating room); their morbidity was 68% and there were six (24%) operative mortalities. Median hospital length of stay (LOS) was 11 days (range, 2-120). Of the 56 patients with contained perforations, 26 were managed successfully without surgery. However, 30 of the patients initially treated nonoperatively eventually required operations due to new pleural effusion, mediastinal abscess, or conversion to noncontained perforation. Their morbidity was 41% and there were three operative mortalities (5%). On univariate analysis, these patients were more likely to have undergone previous esophageal procedures (surgical or dilation) (p=0.03), had new or increased pleural effusion (p=0.04), and had greater than 24h between diagnosis and treatment (p=0.02). Only greater than 24h between diagnosis and treatment remained a significant predictor on multivariate analysis. Their median hospital LOS was 21 days (range, 7-77). CONCLUSION: Contained thoracic esophageal perforations can usually be safely managed nonoperatively without significant morbidity or mortality. However, careful in-hospital monitoring is needed if surgery is not chosen.

Is it safe to perform operation for colorectal malignancy in Chinese patients without DVT prophylaxis? An 8-year experience from a regional hospital in Hong Kong / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Colorectal surgery was regarded as one of the high risk surgery for post-operative deep vein thrombosis (DVT) and pulmonary embolism. This study aimed at investigating the incidence of venous thromboembolism (VTE) after colorectal surgery for malignancy.</p><p><b>METHODS</b>Data were collected from the prospective database of colorectal malignancy from 2000 to 2008. A total of 1421 colorectal (open and laparoscopic) operations were performed for the colorectal malignancy without DVT prophylaxis.</p><p><b>RESULTS</b>Only seven patients (0.5%) developed symptomatic DVT and one of them had complication of pulmonary embolism without mortality. Open operation for colorectal malignancy was identified as possible risk factor of DVT, however, risk factors like operative time, low anterior resection, sex, age etc. were not identified.</p><p><b>CONCLUSION</b>Risk of venous thromboembolism after colorectal operation is low in Chinese of our locality and it might be safe to perform colorectal operation for malignancy without DVT prophylaxis.</p>