Developing and validating subjective and objective risk-assessment measures for predicting mortality after major surgery: An international prospective cohort study.

BACKGROUND: Preoperative risk prediction is important for guiding clinical decision-making and resource allocation. Clinicians frequently rely solely on their own clinical judgement for risk prediction rather than objective measures. We aimed to compare the accuracy of freely available objective surgical risk tools with subjective clinical assessment in predicting 30-day mortality. METHODS AND FINDINGS: We conducted a prospective observational study in 274 hospitals in the United Kingdom (UK), Australia, and New Zealand. For 1 week in 2017, prospective risk, surgical, and outcome data were collected on all adults aged 18 years and over undergoing surgery requiring at least a 1-night stay in hospital. Recruitment bias was avoided through an ethical waiver to patient consent; a mixture of rural, urban, district, and university hospitals participated. We compared subjective assessment with 3 previously published, open-access objective risk tools for predicting 30-day mortality: the Portsmouth-Physiology and Operative Severity Score for the enUmeration of Mortality (P-POSSUM), Surgical Risk Scale (SRS), and Surgical Outcome Risk Tool (SORT). We then developed a logistic regression model combining subjective assessment and the best objective tool and compared its performance to each constituent method alone. We included 22,631 patients in the study: 52.8% were female, median age was 62 years (interquartile range [IQR] 46 to 73 years), median postoperative length of stay was 3 days (IQR 1 to 6), and inpatient 30-day mortality was 1.4%. Clinicians used subjective assessment alone in 88.7% of cases. All methods overpredicted risk, but visual inspection of plots showed the SORT to have the best calibration. The SORT demonstrated the best discrimination of the objective tools (SORT Area Under Receiver Operating Characteristic curve [AUROC] = 0.90, 95% confidence interval [CI]: 0.88-0.92; P-POSSUM = 0.89, 95% CI 0.88-0.91; SRS = 0.85, 95% CI 0.82-0.87). Subjective assessment demonstrated good discrimination (AUROC = 0.89, 95% CI: 0.86-0.91) that was not different from the SORT (p = 0.309). Combining subjective assessment and the SORT improved discrimination (bootstrap optimism-corrected AUROC = 0.92, 95% CI: 0.90-0.94) and demonstrated continuous Net Reclassification Improvement (NRI = 0.13, 95% CI: 0.06-0.20, p < 0.001) compared with subjective assessment alone. Decision-curve analysis (DCA) confirmed the superiority of the SORT over other previously published models, and the SORT-clinical judgement model again performed best overall. Our study is limited by the low mortality rate, by the lack of blinding in the 'subjective' risk assessments, and because we only compared the performance of clinical risk scores as opposed to other prediction tools such as exercise testing or frailty assessment. CONCLUSIONS: In this study, we observed that the combination of subjective assessment with a parsimonious risk model improved perioperative risk estimation. This may be of value in helping clinicians allocate finite resources such as critical care and to support patient involvement in clinical decision-making.

Postoperative critical care and high-acuity care provision in the United Kingdom, Australia, and New Zealand.

BACKGROUND: Decisions to admit high-risk postoperative patients to critical care may be affected by resource availability. We aimed to quantify adult ICU/high-dependency unit (ICU/HDU) capacity in hospitals from the UK, Australia, and New Zealand (NZ), and to identify and describe additional 'high-acuity' beds capable of managing high-risk patients outside the ICU/HDU environment. METHODS: We used a modified Delphi consensus method to design a survey that was disseminated via investigator networks in the UK, Australia, and NZ. Hospital- and ward-level data were collected, including bed numbers, tertiary services offered, presence of an emergency department, ward staffing levels, and the availability of critical care facilities. RESULTS: We received responses from 257 UK (response rate: 97.7%), 35 Australian (response rate: 32.7%), and 17 NZ (response rate: 94.4%) hospitals (total 309). Of these hospitals, 91.6% reported on-site ICU or HDU facilities. UK hospitals reported fewer critical care beds per 100 hospital beds (median=2.7) compared with Australia (median=3.7) and NZ (median=3.5). Additionally, 31.1% of hospitals reported having high-acuity beds to which high-risk patients were admitted for postoperative management, in addition to standard ICU/HDU facilities. The estimated numbers of critical care beds per 100 000 population were 9.3, 14.1, and 9.1 in the UK, Australia, and NZ, respectively. The estimated per capita high-acuity bed capacities per 100 000 population were 1.2, 3.8, and 6.4 in the UK, Australia, and NZ, respectively. CONCLUSIONS: Postoperative critical care resources differ in the UK, Australia, and NZ. High-acuity beds may have developed to augment the capacity to deliver postoperative critical care.

Breath alcohol of anesthesiologists using alcohol hand gel and the "five moments for hand hygiene" in routine practice.

PURPOSE: Appropriate hand hygiene reduces hospital-acquired infections. Anesthesiologists work in environments with numerous hand hygiene opportunities (HHOs). In a prospective observational study, we investigated the potential for an anesthesiologist to return a positive alcohol breath test during routine practice when using alcohol hand gel. METHODS: We observed ten volunteer anesthesiologists over four hours while they implemented the World Health Organization (WHO) "five moments for hand hygiene" using our hospital's adopted standard 70% ethanol hand gel. We measured the expired alcohol concentration at shift start and every fifteen minutes thereafter with a fuel cell breathalyzer calibrated to measure the percentage of blood alcohol concentration (BAC). Blood alcohol specimens (analyzed with gas chromatography) were collected at shift start and, when possible, immediately after a participant's first positive breathalyzer test. RESULTS: Of the 130 breathalyzer tests obtained, there were eight (6.2%) positive breath alcohol results from six of the ten participants, all within two minutes of a HHO. The highest value breathalyzer BAC recorded was 0.064%, with an overall mean (SD) of 0.023 (0.017)%. Five (62.5%) of the positive breathalyzer tests returned to zero in less than seven minutes. All of three blood specimens obtained immediately after a positive breathalyzer reading tested negative for alcohol. CONCLUSION: Anesthesia practitioners using alcohol hand gel in a manner that conforms with recommended hand hygiene can test positive for alcohol on a breathalyzer assay. Positive tests probably arose from inhalation of alcohol vapour into the respiratory dead space following gel application. If workplace breath testing for alcohol is implemented, it should be completed more than 15 min after applying alcohol hand gel. Positive results should be verified with a BAC test.

Robust diagnostic genetic testing using solution capture enrichment and a novel variant-filtering interface.

Targeted hybridization enrichment prior to next-generation sequencing is a widespread method for characterizing sequence variation in a research setting, and is being adopted by diagnostic laboratories. However, the number of variants identified can overwhelm clinical laboratories with strict time constraints, the final interpretation of likely pathogenicity being a particular bottleneck. To address this, we have developed an approach in which, after automatic variant calling on a standard unix pipeline, subsequent variant filtering is performed interactively, using AgileExomeFilter and AgilePindelFilter (http://dna.leeds.ac.uk/agile), tools designed for clinical scientists with standard desktop computers. To demonstrate the method's diagnostic efficacy, we tested 128 patients using (1) a targeted capture of 36 cancer-predisposing genes or (2) whole-exome capture for diagnosis of the genetically heterogeneous disorder primary ciliary dyskinesia (PCD). In the cancer cohort, complete concordance with previous diagnostic data was achieved across 793 variant genotypes. A high yield (42%) was also achieved for exome-based PCD diagnosis, underscoring the scalability of our method. Simple adjustments to the variant filtering parameters further allowed the identification of a homozygous truncating mutation in a presumptive new PCD gene, DNAH8. These tools should allow diagnostic laboratories to expand their testing portfolios flexibly, using a standard set of reagents and techniques.

Genetic diagnosis of familial breast cancer using clonal sequencing.

Using conventional Sanger sequencing as a reference standard, we compared the sensitivity, specificity, and capacity of the Illumina GA II platform for the detection of TP53, BRCA1, and BRCA2 mutations in established tumor cell lines and DNA from patients with germline mutations. A total of 656 coding variants were identified in four cell lines and 65 patient DNAs. All of the known pathogenic mutations (including point mutations and insertions/deletions of up to 16 nucleotides) were identified, using a combination of the Illumina data analysis pipeline with custom and commercial sequence alignment software. In our configuration, clonal sequencing outperforms current diagnostic methods, providing a reduction in analysis times and in reagent costs compared with conventional sequencing. These improvements open the possibility of BRCA1/2 testing for a wider spectrum of at-risk women, and will allow the genetic classification of tumors prior to the use of novel PARP inhibitors to treat BRCA-deficient breast cancers.

The dominant cold-sensitive Out-cold mutants of Drosophila melanogaster have novel missense mutations in the voltage-gated sodium channel gene paralytic.

Here we report the molecular characterization of Out-cold (Ocd) mutants of Drosophila melanogaster, which produce a dominant, X-linked, cold-sensitive paralytic phenotype. From its initial 1.5-Mb cytological location within 13F1-16A2, P-element and SNP mapping reduced the Ocd critical region to <100 kb and to six candidate genes: hangover, CG9947, CG4420, eIF2a, Rbp2, and paralytic (para). Complementation testing with para null mutations strongly suggests Ocd and para are allelic, as does gene rescue of Ocd semilethality with a wild-type para transgene. Pesticide resistance and electrophysiological phenotypes of Ocd mutants support this conclusion. The para gene encodes a voltage-gated sodium channel. Sequencing the Ocd lines revealed mutations within highly conserved regions of the para coding sequence, in the transmembrane segment S6 of domain III (I1545M and T1551I), and in the linker between domains III and IV (G1571R), the location of the channel inactivation gate. The G1571R mutation is of particular interest as mutations of the orthologous residue (G1306) in the human skeletal muscle sodium channel gene SCN4A are associated with cases of periodic paralysis and myotonia, including the human cold-sensitive disorder paramyotonia congenita. The mechanisms by which sodium channel mutations cause cold sensitivity are not well understood. Therefore, in the absence of suitable vertebrate models, Ocd provides a system in which genetic, molecular, physiological, and behavioral tools can be exploited to determine mechanisms underlying sodium channel periodic paralyses.