The Impact of COVID-19 on the Training of Anesthesiologists in Hong Kong: Overcoming the Challenge.

Objectives: This study aimed to investigate the impact of COVID-19 on the training of anesthesiologists in Hong Kong. Introduction: COVID-19 has caused a substantial impact on anesthesiology training in multiple domains. The challenges faced by both trainees and educators remain a significant concern and adaptations in clinical teaching are warranted. We conducted this study to quantify the impact and identify learning areas in recurring pandemics. Methods: Electronic surveys were distributed to anesthesiology trainees and fellows in Hospital Authority in Hong Kong. Data from respondents were collated and analyzed. Reliability analysis and exploratory factor analysis (EFA) were performed. Results: A total of 97 responses were collected and analyzed. Majority (59% of trainees and 79% of fellows) agreed that the COVID-19 pandemic negatively impacted anesthesia training overall. Bag-mask ventilation and direct laryngoscopy were the 2 most affected areas in airway training; 47% of fellows observed a technical skill decline among trainees. Most respondents (64% of trainees and 71% of fellows) agreed that simulation sessions could help with residents' training. Exploratory factor analysis indicated the following subscales: loss of educational opportunities, loss of caseload and formal training, loss of technical skills (regional and procedural), loss of technical skills (airway management), the hampering of ICU rotations, and difficulty teaching residents. Conclusion: The COVID-19 pandemic has caused disruptions in caseload, technical skills training, work-based assessment, and continued medical education, hampering both trainees' and fellows' education. Measures to counter the effect of the pandemic were discussed. Our findings will help educators better understand the challenges, marshal resources, and plan to enhance trainees' educational experience.

Neuraxial versus general anesthesia in elderly patients undergoing hip fracture surgery and the incidence of postoperative delirium: a systematic review and stratified meta-analysis.

BACKGROUND: Evidence-based effect of anesthetic regimens on postoperative delirium (POD) incidence after hip fracture surgery is still debated. Randomized trials have reported inconsistent contradictory results largely attributed to small sample size, use of outdated drugs and techniques, and inconsistent definitions of adverse outcomes. The primary objective of this meta-analysis was to investigate the impact of different anesthesia regimens on POD, cognitive impairment, and associated complications including mortality, duration of hospital stay, and rehabilitation capacity. METHODS: We identified randomized controlled trials (RCTs) published from 2000 to December 2021, in English and non-English language, comparing the effect of neuraxial anesthesia (NA) versus general anesthesia (GA) in elderly patients undergoing hip fracture surgery, from PubMed, EMBASE, Google Scholar, Web of Science and the Cochrane Library database. They were included if POD incidence, cognitive impairment, mortality, duration of hospital stay, or rehabilitation capacity were reported as at least one of the outcomes. Study protocols, case reports, audits, editorials, commentaries, conference reports, and abstracts were excluded. Two investigators (KYC and TXY) independently screened studies for inclusion and performed data extraction. The risk of bias was assessed using the Cochrane Collaboration risk-of-bias tool. The quality of the evidence for each outcome according to the GRADE working group criteria. The odds ratio (OR) and 95% confidence intervals (CI) were calculated to assess the pooled data. RESULTS: A total of 10 RCTs with 3968 patients were included in the present analysis. No significant differences were found in the incidence of POD comparing NA vs GA [OR 1.10, 95% CI (0.89 to 1.37)], with or without including patients with a pre-existing condition of dementia or delirium, POD incidence from postoperative day 2-7 [OR 0.31, 95% CI (0.06 to -1.63)], in mini-mental state examination (MMSE) score [OR 0.07, 95% CI (-0.22 to 0.36)], or other neuropsychological test results. NA appeared to have a shorter duration of hospital stay, especially in patients without pre-existing dementia or delirium, however the observed effect did not reach statistical significance [OR -0.23, 95% CI (-0.46 to 0.01)]. There was no difference in other outcomes, including postoperative pain control, discharge to same preadmission residence [OR 1.05, 95% CI (0.85 to 1.31)], in-hospital mortality [OR 1.98, 95% CI (0.20 to 19.25)], 30-day [OR 1.03, 95% CI (0.47 to 2.25)] or 90-day mortality [OR 1.08, 95% CI (0.53-2.24)]. CONCLUSIONS: No significant differences were detected in incidence of POD, nor in other delirium-related outcomes between NA and GA groups and in subgroup analyses. NA appeared to be associated with a shorter hospital stay, especially in patients without pre-existing dementia, but the observed effect did not reach statistical significance. Further larger prospective randomized trials investigating POD incidence and its duration and addressing long-term clinical outcomes are indicated to rule out important differences between different methods of anesthesia for hip surgery. TRIAL REGISTRATION: 10.17605/OSF.IO/3DJ6C.

High-flow Nasal Cannula versus Conventional Ventilation in Laryngeal Surgery: A Systematic Review and Meta-analysis.

High-flow nasal cannula (HFNC) is an emerging option for maintaining oxygenation in patients undergoing laryngeal surgery, as an alternative to traditional tracheal ventilation and jet ventilation (JV). However, the data on its safety and efficacy is sparse. This study aims to aggregate the current data and compares the use of HFNC with tracheal intubation and jet ventilation in adult patients undergoing laryngeal surgery. We searched PubMed, MEDLINE (Medical Literature Analysis and Retrieval System Online, or MEDLARS Online), Embase (Excerpta Medica Database), Google Scholar, Cochrane Library, and Web of Science. Both observational studies and prospective comparative studies were included. Risk of bias was appraised with the Cochrane Collaboration Risk of Bias in Non-Randomized Studies - of Interventions (ROBINS-I) or RoB2 tools and the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for case series. Data were extracted and tabulated as a systematic review. Summary statistics were performed. Meta-analyses and trial sequential analyses of the comparative studies were performed. Forty-three studies (14 HFNC, 22 JV, and seven comparative studies) with 8064 patients were included. In the meta-analysis of comparative studies, the duration of surgery was significantly reduced in the THRIVE (Transnasal Humidified Rapid-Insufflation Ventilatory Exchange) group, but the number of desaturations, need for rescue intervention, and peak end-tidal CO2 were significantly increased compared to the conventional ventilation group. The evidence was of moderate certainty and there was no evidence of publication bias. In conclusion, HFNC may be as effective as tracheal intubation in oxygenation during laryngeal surgery in selected adult patients and reduces the duration of surgery but conventional ventilation with tracheal intubation may be safer. The safety of JV was comparable to HFNC.

Restricted Versus Liberal Versus Goal-Directed Fluid Therapy for Non-vascular Abdominal Surgery: A Network Meta-Analysis and Systematic Review.

Optimal perioperative fluid management is crucial, with over- or under-replacement associated with complications. There are many strategies for fluid therapy, including liberal fluid therapy (LFT), restrictive fluid therapy (RFT) and goal-directed fluid therapy (GDT), without a clear consensus as to which is better. We aimed to find out which is the more effective fluid therapy option in adult surgical patients undergoing non-vascular abdominal surgery in the perioperative period. This study is a systematic review and network meta-analysis (NMA) with node-splitting analysis of inconsistency, sensitivity analysis and meta-regression. We conducted a literature search of Pubmed, Cochrane Library, EMBASE, Google Scholar and Web of Science. Only studies comparing restrictive, liberal and goal-directed fluid therapy during the perioperative phase in major non-cardiac surgery in adult patients will be included. Trials on paediatric patients, obstetric patients and cardiac surgery were excluded. Trials that focused on goal-directed therapy monitoring with pulmonary artery catheters and venous oxygen saturation (SvO2), as well as those examining purely biochemical and laboratory end points, were excluded. A total of 102 randomised controlled trials (RCTs) and 78 studies (12,100 patients) were included. NMA concluded that goal-directed fluid therapy utilising FloTrac was the most effective intervention in reducing the length of stay (LOS) (surface under cumulative ranking curve (SUCRA) = 91%, odds ratio (OR) = -2.4, 95% credible intervals (CrI) = -3.9 to -0.85) and wound complications (SUCRA = 86%, OR = 0.41, 95% CrI = 0.24 to 0.69). Goal-directed fluid therapy utilising pulse pressure variation was the most effective in reducing the complication rate (SUCRA = 80%, OR = 0.25, 95% CrI = 0.047 to 1.2), renal complications (SUCRA = 93%, OR = 0.23, 95% CrI = 0.045 to 1.0), respiratory complications (SUCRA = 74%, OR = 0.42, 95% CrI = 0.053 to 3.6) and cardiac complications (SUCRA = 97%, OR = 0.067, 95% CrI = 0.0058 to 0.57). Liberal fluid therapy was the most effective in reducing the mortality rate (SUCRA = 81%, OR = 0.40, 95% CrI = 0.12 to 1.5). Goal-directed therapy utilising oesophageal Doppler was the most effective in reducing anastomotic leak (SUCRA = 79%, OR = 0.45, 95% CrI = 0.12 to 1.5). There was no publication bias, but moderate to substantial heterogeneity was found in all networks. In preventing different complications, except mortality, goal-directed fluid therapy was consistently more highly ranked and effective than standard (SFT), liberal or restricted fluid therapy. The evidence grade was low quality to very low quality for all the results, except those for wound complications and anastomotic leak.

Simple Approach for Reconciling Cyclic Voltammetry with Hydrogen Adsorption Energy for Hydrogen Evolution Exchange Current.

Cyclic voltammetry (CV) is a standard technique to analyze the current-potential characteristics of the hydrogen evolution reaction (HER). Herein, we develop a computational quantum-scaled CV model for the HER building on the Butler-Volmer relation for a one-step, one-charge transfer process. Owing to a universal and absolute rate constant verified by fitting to experimental cyclic voltammograms of elemental metals, we show that the model quantifies the exchange current─the main analytical descriptor for HER activity─solely using the hydrogen adsorption free energy obtained from density functional theory calculations. Furthermore, the model resolves controversies over analytical studies for HER kinetics.

Effect of Anaesthesia Depth on Postoperative Delirium and Postoperative Cognitive Dysfunction in High-Risk Patients: A Systematic Review and Meta-Analysis.

Postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) pose increased morbidity and mortality, especially to elderly patients. The effect of anesthesia is debatable. The databases of PubMed, EMBASE, Google Scholar, Cochrane Library and Web of Science were searched from inception until 24 February 2022 to identify randomized-controlled trials (RCTs) studying the effect of depth of anesthesia on POD and POCD primarily. Data on length of hospital stay and mortality were also extracted. Trial sequential analysis was also performed. Seventeen studies were eligible for systematic review and 15 studies of 5392 patients were eligible for meta-analysis. High bispectral index (BIS) favored a reduction in POD and POCD at three months. We found no significant difference between High BIS and Low BIS for mini-mental state exam (MMSE) score and POCD on day 7. However, this did not translate to a significant difference in length of stay and mortality. The data was also underpowered and heterogeneous. Future RCTs should focus on high-risk patients. A standardized methodology of reporting postoperative delirium and cognitive dysfunction is needed to improve comparisons across trials.

Reconciling the Volcano Trend with the Butler-Volmer Model for the Hydrogen Evolution Reaction.

The volcano trend has been widely utilized to forecast new optimum catalysts in computational chemistry while the Butler-Volmer relationship is the norm to explain current-potential characteristics from cyclic voltammetry in analytical chemistry. Herein, we develop an electrochemical model for hydrogen evolution reaction exchange currents that reconciles device-level chemistry, atomic-level volcano trend, and the Butler-Volmer relation. We show that the model is a function of the easy-to-compute hydrogen adsorption energy invariably obtained from first-principles atomic simulations. In addition, the model reproduces with high fidelity the experimental exchange currents for elemental metal catalysts over 15 orders of magnitude and is consistent with the recently proposed analytical model based on a data-driven approach. Our findings based on fundamental electrochemistry principles are general and can be applied to other reactions including CO2 reduction, metal oxidation, and lithium (de)intercalation reactions.

Revealing High-Temperature Reduction Dynamics of High-Entropy Alloy Nanoparticles via In Situ Transmission Electron Microscopy.

Understanding the behavior of high-entropy alloy (HEA) materials under hydrogen (H2) environment is of utmost importance for their promising applications in structural materials, catalysis, and energy-related reactions. Herein, the reduction behavior of oxidized FeCoNiCuPt HEA nanoparticles (NPs) in atmospheric pressure H2 environment was investigated by in situ gas-cell transmission electron microscopy (TEM). The reduction reaction front was maintained at the external surface of the oxide. During reduction, the oxide layer expanded and transformed into porous structures where oxidized Cu was fully reduced to Cu NPs while Fe, Co, and Ni remained in the oxidized form. In situ chemical analysis showed that the expansion of the oxide layer resulted from the outward diffusion flux of all transition metals (Fe, Co, Ni, Cu). Revealing the H2 reduction behavior of HEA NPs facilitates the development of advanced multicomponent alloys for applications targeting H2 formation and storage, catalytic hydrogenation, and corrosion removal.

In Situ Oxidation Studies of High-Entropy Alloy Nanoparticles.

Although high-entropy alloys (HEAs) have shown tremendous potential for elevated temperature, anticorrosion, and catalysis applications, little is known on how HEA materials behave under complex service environments. Herein, we studied the high-temperature oxidation behavior of Fe0.28Co0.21Ni0.20Cu0.08Pt0.23HEA nanoparticles (NPs) in an atmospheric pressure dry air environment by in situ gas-cell transmission electron microscopy. It is found that the oxidation of HEA NPs is governed by Kirkendall effects with logarithmic oxidation rates rather than parabolic as predicted by Wagner's theory. Further, the HEA NPs are found to oxidize at a significantly slower rate compared to monometallic NPs. The outward diffusion of transition metals and formation of disordered oxide layer are observed in real time and confirmed through analytical energy dispersive spectroscopy, and electron energy loss spectroscopy characterizations. Localized ordered lattices are identified in the oxide, suggesting the formation of Fe2O3, CoO, NiO, and CuO crystallites in an overall disordered matrix. Hybrid Monte Carlo and molecular dynamics simulations based on first-principles energies and forces support these findings and show that the oxidation drives surface segregation of Fe, Co, Ni, and Cu, while Pt stays in the core region. The present work offers key insights into how HEA NPs behave under high-temperature oxidizing environment and sheds light on future design of highly stable alloys under complex service conditions.

Revealing Sintering Kinetics of MoS2-Supported Metal Nanocatalysts in Atmospheric Gas Environments via Operando Transmission Electron Microscopy.

The decoration of two-dimensional (2D) substrates with nanoparticles (NPs) serve as heterostructures for various catalysis applications. Deep understanding of catalyst degradation mechanisms during service conditions is crucial to improve the catalyst durability. Herein, we studied the sintering behavior of Pt and bimetallic Au-core Pt-shell (Au@Pt core-shell) NPs on MoS2 supports at high temperatures under vacuum, nitrogen (N2), hydrogen (H2), and air environments by in situ gas-cell transmission electron microscopy (TEM). The key observations are summarized as effect of environment: while particle migration and coalescence (PMC) was the main mechanism that led to Pt and Au@Pt NPs degradation under vacuum, N2, and H2 environments, the degradation of MoS2 substrate was prominent under exposure to air at high temperatures. Pt NPs were less stable in H2 environment when compared with the Pt NPs under vacuum or N2, due to Pt-H interactions that weakened the adhesion of Pt on MoS2. Effect of NP composition: under H2, the stability of Au@Pt NPs was higher in comparison to Pt NPs. This is because H2 promotes the alloying of Pt-Au, thus reducing the number of Pt at the surface (reducing H2 interactions) and increasing Pt atoms in contact with MoS2. Effect of NP size: The alloying effect promoted by H2 was more pronounced in small size Au@Pt NPs resulting in their higher sintering resistance in comparison to large size Au@Pt NPs and similar size Pt NPs. The present work provides key insights into the parameters affecting the catalyst degradation mechanisms on 2D supports.

Graphene Activation Explains the Enhanced Hydrogen Evolution on Graphene-Coated Molybdenum Carbide Electrocatalysts.

Molybdenum carbides (MoxC) have shown high catalytic activities toward hydrogen evolution reaction (HER) when coupled with graphene. Herein, we use density functional theory (DFT) calculations in conjunction with ab initio thermodynamics and electrochemical modeling on γ-MoC supported graphene to determine the origin of the enhanced HER activities. In addition to previous claims that graphene's main role is to prevent agglomeration of MoxC nanoparticles, we show that the interplay between γ-MoC coupling and graphene defect chemistry activates graphene for the HER. For γ-MoC supported graphene systems, the HER mechanism follows the Volmer-Heyrovsky pathway with the Heyrovsky reaction as the rate-determining step. To simulate the electrochemical linear sweep voltammetry at the device level, we develop a computational current model purely from the thermodynamic and kinetics descriptors obtained using DFT. This model shows that γ-MoC supported graphene with divacancies is optimum for HER with an exchange current density of ∼1 × 10-4 A/cm2 and Tafel slope of ∼50 mV/dec-1, which are in good agreement with experimental results.

Validation of contemporary electrocardiographic indices of area at risk and infarct size in acute ST elevation myocardial infarction (STEMI).

BACKGROUND: Electrocardiographic (ECG) methods to assess area at risk (AAR) and infarct size (IS) in patients with ST-elevation myocardial infarction (STEMI) have been previously established but not validated against contemporary benchmark Cardiac Magnetic Resonance (CMR) measures. We compared ECG-determined and CMR-determined measures for (a) AAR, (b) IS, and (c) myocardial salvage. METHODS: Sixty patients with ECG evidence of STEMI and CMR imaging performed within 13 days were included. The ECG-determined (a) AAR scores (Aldrich and Wilkins), (b) IS (Selvester score), and (c) myocardial salvage (i.e. [AAR-IS] / AAR × 100%), were compared with CMR-determined measures. RESULTS: Compared with CMR-determined AAR, both the Wilkins & Aldrich scores underestimated AAR, although the Wilkins (r = 0.72, p < 0.001) showed a better correlation than the Aldrich (r = 0.54, p < 0.001). Bland-Altman analysis revealed a bias of 2.6% (95% limits of agreement: 18.5%, -13.3%) for the Wilkins and 5.9% (95% limits of agreement: 25.6%, -13.8%) for the Aldrich. Estimation of IS was similar between the Selvester score and CMR, with good correlation (r = 0.77, p < 0.001) and agreement (fixed bias 0.4%, 95% limits of agreement 20.8%, -15.5%). However, ECG-determined myocardial salvage significantly underestimated CMR-determined myocardial salvage, with an inverse correlation (r = -0.33, p = 0.01). CONCLUSIONS: The Wilkins score is superior to Aldrich score as an ECG-AAR index, Selvester score is a reasonable ECG estimate of infarct size, though ECG derived myocardial salvage does not have enough accuracy to be used in the clinical setting; it may be an inexpensive surrogate for myocardial salvage in large research studies. Further validation and prognostic studies are required.

Familial GATA6 mutation causing variably expressed diabetes mellitus and cardiac and renal abnormalities.

A 26-year-old man presented with a combination of permanent neonatal diabetes due to pancreatic aplasia, complex congenital heart disease, central hypogonadism and growth hormone deficiency, structural renal abnormalities with proteinuria, umbilical hernia, neurocognitive impairment and dysmorphic features. His older brother had diabetes mellitus due to pancreatic hypoplasia, complex congenital heart disease, hypospadias and umbilical hernia. Their father had an atrial septal defect, umbilical hernia and diabetes mellitus diagnosed incidentally in adulthood on employment screening. The proband's paternal grandmother had a congenital heart defect. Genetic testing of the proband revealed a novel heterozygous missense variant (Chr18:g.19761441T>C, c.1330T>C, p.Cys444Arg) in exon 4 of GATA6, which is class 5 (pathogenic) using American College of Medical Genetics and Genomics guidelines and is likely to account for his multisystem disorder. The same variant was detected in his brother and father, but not his paternal grandmother. This novel variant of GATA6 likely occurred de novo in the father with autosomal dominant inheritance in the proband and his brother. The case is exceptional as very few families with monogenic diabetes due to GATA6 mutations have been reported to date and we describe a new link between GATA6 and renal pathology. Learning points: Monogenic diabetes should be suspected in patients presenting with syndromic features, multisystem congenital disease, neonatal-onset diabetes and/or a suggestive family history. Recognition and identification of genetic diabetes may improve patient understanding and empowerment and allow for better tailored management. Identification of a genetic disorder may have important implications for family planning.

Achondroplasia with SRY-positive 46, XX disorder of sex development: an extremely rare association.

A 40-year-old man with achondroplasia presented with symptoms of hypogonadism, low libido and gynaecomastia. He was found to have hypergonadotropic hypogonadism, and karyotype and fluorescent in situ hybridisation analysis showed SRY-positive 46, XX disorder of sex development (DSD). He was tested to have the common activating mutation of the FGFR3 gene implicated in achondroplasia, indicating that he had the two rare conditions independently, with an extremely low incidence of 1 in 400 million. This, to the best of our knowledge, is the first report of an individual having these two rare conditions concurrently. This case highlights that individuals with achondroplasia should have normal sexual development, and in those presenting with incomplete sexual maturation or symptoms of hypogonadism should prompt further evaluation. We also propose a plausible link between achondroplasia and 46, XX DSD through the intricate interactions between the SRY, SOX9 and FGFR9 gene pathways. LEARNING POINTS: The SOX9 and FGF9 genes, which are upregulated by the SRY gene, are important in both sex determination in the embryo, as well as endochondral bone growth.Patients with achondroplasia should have normal sexual development and function in the absence of other confounding factors.Patients with achondroplasia who present with symptoms and signs of abnormal sexual development and/or hypogonadism should be appropriately investigated for other causes.

High-volume intensive training course: a new paradigm for video-assisted thoracoscopic surgery education.

OBJECTIVES: The emergence of ultra-high-volume centres promises new opportunities for thoracic surgical training. The goal of this study was to investigate the effectiveness of a novel observership course in teaching video-assisted thoracoscopic surgery (VATS) at an ultra-high-volume centre. METHODS: Two-week courses in VATS at a specialist unit now performing >10 000 major lung resections annually (>50 daily on average) were attended by 230 surgeons from around the world from 2013 to 2016. An online survey preserving responder anonymity was completed by 156 attendees (67.8%). RESULTS: Attendees included 37% from Western Europe, 18% from Eastern Europe and 17% from Latin America. Experience with open thoracic surgery for more than 5 years was reported by 67%, but 79% had less than 5 years of VATS lobectomy experience. During the course, 70% observed over 30 uniportal VATS operations (including 38% observing over 50), and 69% attended an animal wet lab. Although 72% of the responders attended the course less than 12 months ago, the number of ports used (P < 0.001), operation times (P < 0.001) and conversion rates (P < 0.001) reported by the responders were reduced significantly after the course. Improvements in the problem areas of tissue retraction, instrumentation, stapler application and coordination with the assistant during VATS were reported by 56%, 57%, 58% and 53%, respectively. Of those who had attended other VATS courses previously, 87% preferred the training from this high-volume course. CONCLUSIONS: High-volume intensive observership training at an ultra-high-volume centre may improve VATS proficiency in a short period of time, and may provide a time-efficient modality for future thoracic surgical training.

Population genomics and the evolution of virulence in the fungal pathogen Cryptococcus neoformans.

Cryptococcus neoformans is an opportunistic fungal pathogen that causes approximately 625,000 deaths per year from nervous system infections. Here, we leveraged a unique, genetically diverse population of C. neoformans from sub-Saharan Africa, commonly isolated from mopane trees, to determine how selective pressures in the environment coincidentally adapted C. neoformans for human virulence. Genome sequencing and phylogenetic analysis of 387 isolates, representing the global VNI and African VNB lineages, highlighted a deep, nonrecombining split in VNB (herein, VNBI and VNBII). VNBII was enriched for clinical samples relative to VNBI, while phenotypic profiling of 183 isolates demonstrated that VNBI isolates were significantly more resistant to oxidative stress and more heavily melanized than VNBII isolates. Lack of melanization in both lineages was associated with loss-of-function mutations in the BZP4 transcription factor. A genome-wide association study across all VNB isolates revealed sequence differences between clinical and environmental isolates in virulence factors and stress response genes. Inositol transporters and catabolism genes, which process sugars present in plants and the human nervous system, were identified as targets of selection in all three lineages. Further phylogenetic and population genomic analyses revealed extensive loss of genetic diversity in VNBI, suggestive of a history of population bottlenecks, along with unique evolutionary trajectories for mating type loci. These data highlight the complex evolutionary interplay between adaptation to natural environments and opportunistic infections, and that selection on specific pathways may predispose isolates to human virulence.

The Advent of Ultra-high Volume Thoracic Surgical Centers in Shanghai.

BACKGROUND: A core principle in surgery is that high surgical volumes are conducive toward better outcomes. Ultra-high volume centers (UHVCs) have now emerged in thoracic surgery in China that now perform a volume of thoracic operations far greater than even traditional international centers of excellence. METHODS: In 2016, two hospitals in Shanghai performed over 10,000 major pulmonary, esophageal and mediastinal resections each. A qualitative analysis of the lessons learned in achieving such large operation volumes was undertaken. RESULTS: The advent of these UHVCs gives important insights for not only thoracic surgeons, but for surgical oncologists and surgeons globally. First, these ultra-high volumes were achieved to a large degree by cancer screening-but the success of the screening programs relies on reaching wider patient groups and allowing for affordable 'self-screening.' Second, the ultra-high clinical volumes at UHVCs offer unique opportunities for surgical training and research, potentially changing paradigms for academic surgery. Third, these ultra-high volumes may place new stresses on existing healthcare resources and prompt novel management strategies in response. CONCLUSIONS: The UHVCs represent a revolutionary development in modern surgery, and it behooves surgeons to both accept the challenges and harness the advantages they may bring.

Early Use of N-acetylcysteine With Nitrate Therapy in Patients Undergoing Primary Percutaneous Coronary Intervention for ST-Segment-Elevation Myocardial Infarction Reduces Myocardial Infarct Size (the NACIAM Trial [N-acetylcysteine in Acute Myocardial Infarction]).

BACKGROUND: Contemporary ST-segment-elevation myocardial infarction management involves primary percutaneous coronary intervention, with ongoing studies focusing on infarct size reduction using ancillary therapies. N-acetylcysteine (NAC) is an antioxidant with reactive oxygen species scavenging properties that also potentiates the effects of nitroglycerin and thus represents a potentially beneficial ancillary therapy in primary percutaneous coronary intervention. The NACIAM trial (N-acetylcysteine in Acute Myocardial Infarction) examined the effects of NAC on infarct size in patients with ST-segment-elevation myocardial infarction undergoing percutaneous coronary intervention. METHODS: This randomized, double-blind, placebo-controlled, multicenter study evaluated the effects of intravenous high-dose NAC (29 g over 2 days) with background low-dose nitroglycerin (7.2 mg over 2 days) on early cardiac magnetic resonance imaging-assessed infarct size. Secondary end points included cardiac magnetic resonance-determined myocardial salvage and creatine kinase kinetics. RESULTS: Of 112 randomized patients with ST-segment-elevation myocardial infarction, 75 (37 in NAC group, 38 in placebo group) underwent early cardiac magnetic resonance imaging. Median duration of ischemia pretreatment was 2.4 hours. With background nitroglycerin infusion administered to all patients, those randomized to NAC exhibited an absolute 5.5% reduction in cardiac magnetic resonance-assessed infarct size relative to placebo (median, 11.0%; [interquartile range 4.1, 16.3] versus 16.5%; [interquartile range 10.7, 24.2]; P=0.02). Myocardial salvage was approximately doubled in the NAC group (60%; interquartile range, 37-79) compared with placebo (27%; interquartile range, 14-42; P<0.01) and median creatine kinase areas under the curve were 22 000 and 38 000 IU·h in the NAC and placebo groups, respectively (P=0.08). CONCLUSIONS: High-dose intravenous NAC administered with low-dose intravenous nitroglycerin is associated with reduced infarct size in patients with ST-segment-elevation myocardial infarction undergoing percutaneous coronary intervention. A larger study is required to assess the impact of this therapy on clinical cardiac outcomes. CLINICAL TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry. URL: http://www.anzctr.org.au/. Unique identifier: 12610000280000.

Seizure induced by sudden cessation of pregabalin in a patient with chronic kidney disease.

A middle-aged woman with diabetic nephropathy on pregabalin for neuropathic pain presented with a diarrhoeal illness. She was found to have acute on chronic renal impairment with an estimated glomerular filtration rate (eGFR) of 10 mL/min, and her usual 150 mg/day of pregabalin was abruptly ceased. Although renal recovery to her baseline of eGFR 15 mL/min was achieved within 3 days, her pregabalin was not restarted. She suffered a tonic-clonic seizure 4 days later, thought to be due to pregabalin withdrawal as there were no other likely causes identified. She suffered no further seizures on recommencement of pregabalin at a renally adjusted dose of 75 mg/day.

Microevolution of Serial Clinical Isolates of Cryptococcus neoformans var. grubii and C. gattii.

The pathogenic species of Cryptococcus are a major cause of mortality owing to severe infections in immunocompromised as well as immunocompetent individuals. Although antifungal treatment is usually effective, many patients relapse after treatment, and in such cases, comparative analyses of the genomes of incident and relapse isolates may reveal evidence of determinative, microevolutionary changes within the host. Here, we analyzed serial isolates cultured from cerebrospinal fluid specimens of 18 South African patients with recurrent cryptococcal meningitis. The time between collection of the incident isolates and collection of the relapse isolates ranged from 124 days to 290 days, and the analyses revealed that, during this period within the patients, the isolates underwent several genetic and phenotypic changes. Considering the vast genetic diversity of cryptococcal isolates in sub-Saharan Africa, it was not surprising to find that the relapse isolates had acquired different genetic and correlative phenotypic changes. They exhibited various mechanisms for enhancing virulence, such as growth at 39°C, adaptation to stress, and capsule production; a remarkable amplification of ERG11 at the native and unlinked locus may provide stable resistance to fluconazole. Our data provide a deeper understanding of the microevolution of Cryptococcus species under pressure from antifungal chemotherapy and host immune responses. This investigation clearly suggests a promising strategy to identify novel targets for improved diagnosis, therapy, and prognosis.IMPORTANCE Opportunistic infections caused by species of the pathogenic yeast Cryptococcus lead to chronic meningoencephalitis and continue to ravage thousands of patients with HIV/AIDS. Despite receiving antifungal treatment, over 10% of patients develop recurrent disease. In this study, we collected isolates of Cryptococcus from cerebrospinal fluid specimens of 18 patients at the time of their diagnosis and when they relapsed several months later. We then sequenced and compared the genomic DNAs of each pair of initial and relapse isolates. We also tested the isolates for several key properties related to cryptococcal virulence as well as for their susceptibility to the antifungal drug fluconazole. These analyses revealed that the relapsing isolates manifested multiple genetic and chromosomal changes that affected a variety of genes implicated in the pathogenicity of Cryptococcus or resistance to fluconazole. This application of comparative genomics to serial clinical isolates provides a blueprint for identifying the mechanisms whereby pathogenic microbes adapt within patients to prolong disease.