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Objective: Protocol to explore what is known about communication between critical care providers and patients and families from culturally and linguistically diverse backgrounds (defined as people who are either from minority ethnic groups, non-English-speaking backgrounds who may have diverse cultural, linguistic, spiritual and religious affiliations and opinions) about death, dying, end-of-life care and organ donation in the intensive care unit (ICU)., Introduction: Patients from culturally and linguistically diverse backgrounds experience barriers to optimised care when admitted to the ICU. These barriers appear to derive from differences in language, cultural, societal and ethical expectations between patients, their families and healthcare professionals. These barriers may significantly impact the delivery of end-of-life care to patients from culturally and linguistically diverse backgrounds. Therefore, this has the potential for inadequate management of medical, psychological and existential distress., Inclusion Criteria: Studies of all designs reporting for adult (age ≥18 years) patients and family members from culturally and linguistically diverse backgrounds at end-of-life in the ICU setting will be included. Studies that report results for patients aged <18 years or that are based outside the ICU will be excluded., Methods: Relevant sources will be retrieved, and their citation details will be imported into the Joanna Briggs Institute (JBI) System for the Unified Management, Assessment and Review of Information. This scoping review was guided by the JBI methodology for scoping reviews and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews guidelines. A systematic search was conducted in EBSCOhost, Web of Science, PubMed Central and SciELO, OVID Medline, CINAHL, and Scopus, limited to English-language publications, without date limitation. Key study characteristics and findings will be extracted using a data extraction tool developed by the reviewers. Anticipating heterogeneous study designs, findings will be presented as a thematic synthesis., Ethics and Dissemination: This is a protocol for a scoping review, formal ethics approval from the Human Research Ethics Committee (HREC) of the Local Health Network will be obtained for research projects that could potentially stem from this review and will then be subsequently disseminated through proper channels., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To compare time to relapse in patients with major depressive disorder (MDD) stabilised on antidepressant treatment (ADT) + brexpiprazole who were randomised to continued adjunctive brexpiprazole or brexpiprazole withdrawal (switch to placebo)., Methods: This Phase 3, multicentre, double-blind, placebo-controlled, parallel-arm, randomised withdrawal study enrolled adults with MDD and inadequate response to 2–3 ADTs. All patients started on adjunctive brexpiprazole 2–3 mg/day (Phase A, 6–8 weeks). Patients whose symptoms stabilised (Phase B, 12 weeks) were randomised 1:1 to adjunctive brexpiprazole or adjunctive placebo (Phase C, 26 weeks). The primary endpoint was time to relapse in Phase C. Depression rating scale score changes were secondary endpoints., Results: 1149 patients were enrolled and 489 patients were randomised (ADT + brexpiprazole n = 240; ADT + placebo n = 249). Median time to relapse was 63 days from randomisation in both treatment groups for patients who received ≥1 dose. Relapse criteria were met by 22.5% of patients (54/240) on ADT + brexpiprazole and 20.6% (51/248) on ADT + placebo (hazard ratio, 1.14; 95% confidence interval, 0.78–1.67; p = 0.51, log-rank test). Depression scale scores improved during Phases A–B and were maintained in Phase C. Mean weight increased by 2.2 kg in Phases A–B and stabilised in Phase C., Conclusion: Time to relapse was similar between continued adjunctive brexpiprazole and brexpiprazole withdrawal; in both groups, ∼80% of stabilised patients remained relapse free at their last visit. Adjunctive brexpiprazole therapy was generally well tolerated over up to 46 weeks, with minimal adverse effects following brexpiprazole withdrawal.ClinicalTrials.gov identifier: NCT03538691. Funding: Otsuka, Lundbeck.

Objective: To identify immunological pathways and markers of severity of illness associated with clinical outcomes that may represent potential therapeutic targets in the management of secondary hemophagocytic lymphohistiocytosis., Introduction: A broad range of immunomodulatory therapies is used to manage hemophagocytic lymphohistiocytosis, however the supporting evidence for these therapies is scarce. Identifying patients likely to experience more severe disease, or die, is currently extremely difficult, if not impossible. The identification of implicated cytokines in secondary disease can provide further support for the identification of high-risk patients and the development of targeted therapies., Inclusion Criteria: Studies reporting immune biomarker and cytokine measurement in adult patients (age >18 years) with secondary hemophagocytic lymphohistiocytosis., Methods: The proposed review will be conducted in line with the JBI methodology for scoping reviews. The MEDLINE (Ovid) and Embase (Ovid) databases will be searched, without date limitations. Data will be extracted using a data extraction tool developed by the reviewers. Relevant sources will be retrieved, and their citation details imported into the JBI System for the Unified Management, Assessment and Review of Information., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 JBI.)

We recently developed directed methylation with long-read sequencing (DiMeLo-seq) to map protein-DNA interactions genome wide. DiMeLo-seq is capable of mapping multiple interaction sites on single DNA molecules, profiling protein binding in the context of endogenous DNA methylation, identifying haplotype-specific protein-DNA interactions and mapping protein-DNA interactions in repetitive regions of the genome that are difficult to study with short-read methods. With DiMeLo-seq, adenines in the vicinity of a protein of interest are methylated in situ by tethering the Hia5 methyltransferase to an antibody using protein A. Protein-DNA interactions are then detected by direct readout of adenine methylation with long-read, single-molecule DNA sequencing platforms such as Nanopore sequencing. Here we present a detailed protocol and practical guidance for performing DiMeLo-seq. This protocol can be run on nuclei from fresh, lightly fixed or frozen cells. The protocol requires 1-2 d for performing in situ targeted methylation, 1-5 d for library preparation depending on desired fragment length and 1-3 d for Nanopore sequencing depending on desired sequencing depth. The protocol requires basic molecular biology skills and equipment, as well as access to a Nanopore sequencer. We also provide a Python package, dimelo, for analysis of DiMeLo-seq data., (© 2024. Springer Nature Limited.)

Background: The belief that cannabis has analgesic and anti-inflammatory properties continues to attract patients with chronic musculoskeletal (MSK) pain towards its use. However, the role that cannabis will play in the management of chronic MSK pain remains to be determined. This study examined 1) the rate, patterns of use, and self-reported efficacy of cannabis use among patients with chronic MSK pain and 2) the interest and potential barriers to cannabis use among patients with chronic MSK pain not currently using cannabis., Methods: Self-reported cannabis use and perceived efficacy were prospectively collected from chronic MSK pain patients presenting to the Orthopaedic Clinic at the University Health Network, Toronto, Canada. The primary dependent variable was current or past use of cannabis to manage chronic MSK pain; bivariate and multivariable logistic regression were used to identify patient characteristics independently associated with this outcome. Secondary outcomes were summarized descriptively, including self-perceived efficacy among cannabis users, and interest as well as barriers to cannabis use among cannabis non-users., Results: The sample included 629 patients presenting with chronic MSK pain (mean age: 56±15.7 years; 56% female). Overall, 144 (23%) reported past or present cannabis use to manage their MSK pain, with 63.7% perceiving cannabis as very or somewhat effective and 26.6% considering it as slightly effective. The strongest predictor of cannabis use in this study population was a history of recreational cannabis use (OR 12.7, p<0.001). Among cannabis non-users (N=489), 65% expressed interest in using cannabis to manage their chronic MSK pain, but common barriers to use included lack of knowledge regarding access, use and evidence, and stigma., Conclusions: One in five patients presenting to an orthopaedic surgeon with chronic MSK pain are using or have used cannabis with the specific intent to manage their pain, and most report it to be effective. Among non-users, two-thirds reported an interest in using cannabis to manage their MSK pain, but common barriers to use existed. Future double-blind placebo-controlled trials are required to understand if this reported efficacy is accurate, and what role, if any, cannabis may play in the management of chronic MSK pain., (© 2024. The Author(s).)

Background: Gastrointestinal (GI) complications after cardiac surgery are associated with high morbidity and mortality. Early identification and treatment of GI complications could improve patient outcomes., Objectives: The objective of this study was to ascertain the incidence, risk factors, and clinical outcomes of GI complications following cardiac surgery., Methods: A retrospective single-centre cohort study of adult patients undergoing cardiac surgery in an Australian quaternary cardiothoracic surgical referral centre was conducted from November 2012 to March 2020. Preoperative, intraoperative, and postoperative characteristics were compared between patients who did and did not develop GI complications. Data are presented as n (%). Between-group comparisons were analysed using Chi-square and Fisher's exact tests (where n < 6) for categorical variables and Wilcoxon rank-sum test for continuous variables., Results: Of the 4417 patients who underwent cardiac surgery, 95 (2.2%) patients developed a total of 100 GI complications, with the most common being paralytic ileus (n = 22/100, 22%). Baseline characteristics and preoperative factors associated with GI complications included an age of >70 years (GI complication vs no GI complication: 55.8% vs 37.6%; p = 0.000), preexisting diabetes (49.5% vs 34.5%; p = 0.002), and a creatinine level >200 mcg/ml (11.6% vs 3.7%; p = 0.000). Intra-operative factors included a cardiopulmonary bypass time >120 min (28.4% vs 15.5%; p < 0.01). Postoperatively, developing a GI complication was associated with return to theatre (36.8% vs 13.9%; p < 0.01) and new stroke, pneumonia, and acute kidney injury (all p < 0.01). Patients with a GI complication had a higher intensive care unit and hospital mortality (7.4% vs 1.1%, and 13.6% vs 1.4%, respectively), and a longer intensive care unit and hospital stay (5.5 vs 2.3 days, and 24.0 vs 10.3 days)., Conclusions: Multiple risk factors associated with GI complications in cardiac surgery patients were identified. These provide potential targets to support the early detection and management of GI complications to reduce morbidity and mortality in these patients., (Crown Copyright © 2023. Published by Elsevier Ltd. All rights reserved.)

N 2 O is a classic prototype, in which central nitrogen is sufficiently electropositive with a positive potential of 20 kcal mol -1 in magnitude to qualify it as a possible pnicogen. This was applied to a test with N 2 O clusters using ab initio calculations in association with various molecular topographic tools. The structure of the energetically dominant and N 2 O dimer was in favor of a perpendicular geometry, where the central nitrogen atom of the N 2 O submolecule assumed a near 90° angle with the adjacent N═O and/or N═N moiety, which provides the affirmation of central nitrogen as a possible π-hole-driven pnicogen. The terminal nitrogen and oxygen atoms of N 2 O continue to act as conventional electron donors (Lewis bases) with a negative potential. Overall, predominant π-hole-driven N···O and N···N pnicogen bonding interactions were observed to stabilize N 2 O clusters. Furthermore, N 2 O clusters (dimers and trimers) were synthesized at low temperatures in an Ar matrix using molecular beam (effusive and supersonic expansion) experiments. The geometries of these clusters were characterized by probing infrared spectroscopy with corroboration from ab initio computational methods. In addition to our previously investigated nitromethane and nitrobenzene systems, N 2 O also makes it to a pnicogen bonder's club with the central nitrogen as a π-hole-driven pnicogen.

Background: The association between frailty and short-term and long-term outcomes in patients receiving elective surgery for cancer remains unclear, particularly in those admitted to the ICU., Methods: In this multicentre retrospective cohort study, we included adults ≥16 yr old admitted to 158 ICUs in Australia from January 1, 2018 to March 31, 2022 after elective surgery for cancer. We investigated the association between frailty and survival time up to 4 yr (primary outcome), adjusting for a prespecified set of covariates. We analysed how this association changed in specific subgroups (age categories [<65, 65-80, ≥80 yr], and those who survived hospitalisation), and over time by splitting the survival information at monthly intervals., Results: We included 35,848 patients (median follow-up: 18.1 months [inter-quartile range: 8.3-31.1 months], 19,979 [56.1%] male, median age 69.0 yr [inter-quartile range: 58.8-76.0 yr]). Some 3502 (9.8%) patients were frail (defined as clinical frailty scale ≥5). Frailty was associated with lower survival (hazard ratio: 1.72, 95% confidence interval [CI]: 1.59-1.86 compared with clinical frailty scale ≤4); this was concordant across several sensitivity analyses. Frailty was most strongly associated with mortality early on in follow-up, up to 10 months (hazard ratio: 1.39, 95% CI: 1.03-1.86), but this association plateaued, and its predictive capacity subsequently diminished with time up until 4 yr (1.96, 95% CI: 0.73-5.28). Frailty was associated with similar effects when stratified based on age, and in those who survived hospitalisation., Conclusions: Frailty was associated with poorer outcomes after an ICU admission after elective surgery for cancer, particularly in the short term. However, its predictive capacity with time diminished, suggesting a potential need for longitudinal reassessment to ensure appropriate prognostication in this population., (Crown Copyright © 2024. Published by Elsevier Ltd. All rights reserved.)

Background Context: Wait time for surgeries can be lengthy and its effect on postoperative outcome remains largely unknown., Purpose: We evaluated the effect of wait time on postoperative outcome and on clinical course while awaiting surgery for lumbar spinal stenosis., Study Design/setting: This was a retrospective cohort study., Patient Sample: A convenience sample (n=134) from prospective longitudinal studies that provided preoperative Oswestry Disability Index (ODI) data at two different time points and follow-up of ≥12 months., Methods: Wait time was the period between the initial consultation and immediately preoperatively., Outcome Measures: The primary outcome was the ODI minimal clinically important difference (MCID) (<30% vs ≥30% improvement) at 1 year., Results: The median wait time was 5.9 (interquartile range (IQR) 8.2) months and postoperative follow-up was 19.2 (IQR 8.1) months. Wait time was not associated with absolute postoperative change in ODI scores, but patients with wait times <12 months were significantly more likely to reach the ODI MCID at last follow-up (66 (73.3%) for <12 months versus 13 (46.4%) for ≥12 months, p=.008; odds ratio=0.29 (95% confidence interval 0.12-0.75), p=.011). During wait time, there was no difference in patients deteriorating above the MCID for each time point (10 [9.7%] versus 5 [16.1%], p=.320)., Conclusions: Longer wait times did not negatively influence postoperative outcome in patients with lumbar spinal stenosis using absolute values, but may impact individual patients' ability to achieve MCID. Patient-reported pain-related disability from the initial surgical consultation to surgery is relatively stable in most patients for at least 6 to 12 months., Competing Interests: Declaration of competing interest YRR is a consultant for and receives royalties from Medtronic. He is the Chief Medical Officer for Arthur Health Corporation. These potential conflicts of interest did not impact this manuscript., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Studies comparing percutaneous tracheostomy (PT) and surgical tracheostomy (ST) complications in the critically ill patient population with high acuity, complexity, and severity of illness are sparse. This study evaluated the outcomes of elective PT versus ST in such patients managed at a quaternary referral center., Aims: The primary aim was to detect a difference in hospital mortality between the two techniques. The secondary aims were to compare Intensive Care Unit (ICU) mortality, complications (including stoma site, tracheostomy-related, and decannulation complications), ICU and hospital length of stay, and time to decannulation., Methods: This was a single-center retrospective observational study of ICU admission from August 2018 to August 2021. Patients were included if an elective tracheostomy was performed during their ICU admission. Patients with a pre-existing tracheostomy and those who underwent an obligatory tracheostomy requirement (e.g. total laryngectomy) were excluded. Cohorts were matched using Hainmueller's entropy balancing. Binary data were evaluated using logistic regression and continuous data with ordinary least squares regression., Results: 349 patients with a tracheostomy were managed in the ICU during the observation period. They were predominantly males (75% in PT; 67% in ST), with a mean age in the PT and ST group of (47; SD = 18) and (55; SD = 16), respectively. After exclusion, 135 patients remained, with 63 in the PT group and 72 in the ST group. Patients receiving ST were significantly older with a higher Body Mass Index (BMI) than the PT group. There were no significant differences in gender, Acute Physiological And Chronic Health Evaluation (APACHE) III, and the Australian and New Zealand Risk Of Death (ANZROD) between the two groups. There was no difference in hospital mortality between groups (OR 0.91, CI 0.26-3.18, p  = 0.88). There were also no differences in ICU mortality, ICU and hospital length of stay, and time to decannulation. PT was associated with a greater likelihood of complications (OR 4.19; 95% CI 1.73-10.13; p  < 0.01). PT was associated with a greater risk of complications in those who had this performed early (<10 days of intubation) as well as late (>10 days of intubation)., Conclusions: Percutaneous tracheostomy was associated with higher complications compared to surgical tracheostomy. They were related to tracheostomy cuff deflation, stomal site bleeding and infection, sputum plugging, and accidental and failed decannulation. These findings have identified opportunities to improve patient outcomes., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Intensive Care Society 2024.)

Objective: We aimed to describe the characteristics, outcomes and resource utilisation of patients being cared for in an ICU after undergoing elective surgery in Australia and New Zealand (ANZ)., Methods: This was a point prevalence study involving 51 adult ICUs in ANZ in June 2021. Patients met inclusion criteria if they were being treated in a participating ICU on he study dates. Patients were categorised according to whether they had undergone elective surgery, admitted directly from theatre or unplanned from the ward. Descriptive and comparative analysis was performed according to the source of ICU admission. Resource utilisation was measured by Length of stay, organ support and occupied bed days., Results: 712 patients met inclusion criteria, with 172 (24%) have undergone elective surgery. Of these, 136 (19%) were admitted directly to the ICU and 36 (5.1%) were an unplanned admission from the ward. Elective surgical patients occupied 15.8% of the total ICU patient bed days, of which 44.3% were following unplanned admissions. Elective surgical patients who were an unplanned admission from the ward, compared to those admitted directly from theatre, had a higher severity of illness (AP2 17 vs 13, p<0.01), require respiratory or vasopressor support (75% vs 44%, p<0.01) and hospital mortality (16.7% vs 2.2%, p < 0.01)., Conclusions: ICU resource utilisation of patients who have undergone elective surgery is substantial. Those patients admitted directly from theatre have good outcomes and low resource utilisation. Patient admitted unplanned from the ward, although fewer, were sicker, more resource intensive and had significantly worse outcomes., (Crown Copyright © 2023 Published by Elsevier B.V. on behalf of College of Intensive Care Medicine of Australia and New Zealand.)

Objective: To compare long-term psychological symptoms and health-related quality of life (HRQOL) in intubated versus non-intubated ICU survivors., Design: Prospective, multicentre observational cohort study., Setting: Four tertiary medical-surgical ICUs in Australia., Participants: Intubated and non-intubated adult ICU survivors., Main Outcome Measures: Primary outcomes : clinically significant psychological symptoms at 3- and 12-month follow-up using Post-Traumatic Stress Syndrome-14 for post-traumatic stress disorder; Depression, Anxiety Stress Scales-21 for depression, anxiety, and stress. Secondary outcomes : HRQOL, using EuroQol-5D-5L questionnaire., Results: Of the 133 ICU survivors, 54/116 (47 %) had at least one clinically significant psychological symptom (i.e., post-traumatic stress disorder, anxiety, depression, stress) at follow-up. Clinically significant scores for psychological symptoms were observed in 26 (39 %) versus 16 (32 %) at 3-months [odds ratio 1.4, 95 % confidence interval (0.66-3.13), p = 0.38]; 23 (37 %) versus 10 (31 %) at 12-months [odds ratio 1.3, 95 % confidence interval (0.53-3.31), p = 0.57] of intubated versus non-intubated survivors, respectively. Usual activities and mobility were the most commonly affected HRQOL dimension, with >30 % at 3 versus months and >20 % at 12-months of overall survivors reporting ≥ moderate problems. There was no difference between the groups in any of the EQ5D dimensions., Conclusions: Nearly one-in-two (47 %) of the intubated and non-intubated ICU survivors reported clinically significant psychological symptoms at 3 and 12-month follow-ups. Overall, more than 30 % at 3-months and over 20 % at 12-months of the survivors in both groups had moderate or worse problems with their usual activities and mobility. The presence of psychological symptoms and HRQOL impairments was similar between the groups., (© 2023 The Authors.)

Of the total intensive care unit (ICU) admissions in Australia and New Zealand, 36.6% occur following an elective surgical procedure. How best to use ICU services in this setting is not clear, despite this being an expensive and resource-intensive method of care delivery. The literature relating to this area has not demonstrated a clear association between improved outcomes and routine ICU utilisation. It has, however, demonstrated that methods of care delivery in this setting vary at the local, national and international level. There is now an increased interest in how we can offer safe, efficient care to patients who need ICU-level support after elective surgery, as well as where and when that care can be offered. We had previously performed a literature review relating to ICU utilisation in the elective surgical post-operative setting. This perspective piece arises from this literature review as well as extensive clinical experience from the authors. We discuss the need for a move towards an evidence-based indication for ICU admission and how this may be achieved. We then move on to the various alternative models of care that could be offered, briefly discussing their positives and potential drawbacks. We finish by outlining the research priorities and how these might be implemented in clinical practice. Getting the balance right between ICU admission and higher acuity ward-level care for post-operative elective surgical patients is difficult. However, this is an important challenge that we as a healthcare community must be working to answer.

Background: Recent advances in cancer therapeutics have improved outcomes, resulting in increasing candidacy of patients with metastatic cancer being admitted to intensive care units (ICUs). A large proportion of patients also have frailty, predisposing them to poor outcomes, yet the literature reporting on this is scarce. We aimed to assess the impact of frailty on survival in patients with metastatic cancer admitted to the ICU., Methods: In this retrospective registry-based cohort study, we used data from the Australia and New Zealand Intensive Care Society Adult Patient (age ≥16 years) database to identify patients with advanced (solid and haematological cancer) and a documented Clinical Frailty scale (CFS) admitted to 166 Australian ICUs. Patients without metastatic cancer were excluded. We analysed the effect of frailty (CFS 5-8) on long-term survival, and how this effect changed in specific subgroups (cancer subtypes, age [<65 years or ≥65 years], and those who survived hospitalisation). Because estimates tend to cluster within centres and vary between them, we used Cox proportional hazards regression models with robust sandwich variance estimators to assess the effect of frailty on survival time up to 4 years after ICU admission between groups., Findings: Between Jan 1, 2018, and March 31, 2022, 30 026 patients were eligible, and after exclusions 21 174 patients were included in the analysis; of these, 6806 (32·1%) had frailty, and 11 662 (55·1%) were male, 9489 (44·8%) were female, and 23 (0·1%) were intersex or self-reported indeterminate sex. The overall survival was lower for patients with frailty at 4 years compared with patients without frailty (29·5% vs 10·9%; p<0·0001). Frailty was associated with shorter 4-year survival times (adjusted hazard ratio 1·52 [95% CI 1·43-1·60]), and this effect was seen across all cancer subtypes. Frailty was associated with shorter survival times in patients younger than 65 years (1·66 [1·51-1·83]) and aged 65 years or older (1·40 [1·38-1·56]), but its effects were larger in patients younger than 65 years (p interaction <0·0001). Frailty was also associated with shorter survival times in patients who survived hospitalisation (1·49 [1·40-1·59])., Interpretation: In patients with metastatic cancer admitted to the ICU, frailty was associated with poorer long-term survival. Patients with frailty might benefit from a goal-concordant time-limited trial in the ICU and will need suitable post-intensive care supportive management., Funding: None., Competing Interests: Declaration of interests MA reports travel expenses and advisory board fees from Pfizer and MSD and has been a member of a steering committee for the CP-MGA271 trial (MacroGenics). RRL reports a Dean's Research Development award from National University of Singapore, Singapore. RS reports research grants from Paxman Coolers, MSD, and Natera; consulting fees from Bristol Myers Squibb, Merck, Eisai, Bayer, Taiho, Novartis, GSK, Diethelm Keller Siber Hegner, and Astellas; honoraria from MSD, Eli Lilly, Bristol Myers Squibb, Roche, Taiho, AstraZeneca, Diethelm Keller Siber Hegner, and Ipsen; travel expenses from Roche, AstraZeneca, Taiho, Eisai, and Diethelm Keller Siber Hegner; and patents support from Paxman and Auristone. DP chairs the ANZICS Centre for Outcomes and Resource Evaluation Clinical Quality Registry (the data custodian for the present study); is a Vice-President and Board Member of ANZICS; and has been a clinical lead for Safer Care Victoria Critical Care network. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: The incremental hospital cost and length of stay (LOS) associated with adverse events (AEs) has not been well characterized for planned and unplanned inpatient spine, hip, and knee surgeries., Methods: Retrospective cohort study of hip, knee, and spine surgeries at an academic hospital in 2011-2012. Adverse events were prospectively collected for 3,063 inpatient cases using the Orthopaedic Surgical AdVerse Event Severity (OrthoSAVES) reporting tool. Case costs were retrospectively obtained and inflated to equivalent 2021 CAD values. Propensity score methodology was used to assess the cost and LOS attributable to AEs, controlling for a variety of patient and procedure factors., Results: The sample was 55% female and average age was 64; 79% of admissions were planned. 30% of cases had one or more AEs (82% had low-severity AEs at worst). The incremental cost and LOS attributable to AEs were $8,500 (95% confidence interval [CI]: 5100-11,800) and 4.7 days (95% CI: 3.4-5.9) per admission. This corresponded to a cumulative $7.8 M (14% of total cohort cost) and 4,290 bed-days (19% of cohort bed-days) attributable to AEs. Incremental estimates varied substantially by (1) admission type (planned: $4,700/2.4 days; unplanned: $20,700/11.5 days), (2) AE severity (low: $4,000/3.1 days; high: $29,500/11.9 days), and (3) anatomical region (spine: $19,800/9 days; hip: $4,900/3.8 days; knee: $1,900/1.5 days). Despite only 21% of admissions being unplanned, adverse events in these admissions cumulatively accounted for 59% of costs and 62% of bed-days attributable to AEs., Conclusions: This study comprehensively demonstrates the considerable cost and LOS attributable to AEs in orthopaedic and spine admissions. In particular, the incremental cost and LOS attributable to AEs per admission were almost five times as high among unplanned admissions compared to planned admissions. Mitigation strategies focused on unplanned surgeries may result in significant quality improvement and cost savings in the healthcare system., (© 2023. BioMed Central Ltd., part of Springer Nature.)

The nitrogen of nitro group is a paradigmatic pnictogen due the presence of a π-hole and a number of studies have been performed recently on prototypical nitromethane (NM). Homodimers and heterodimers of NM are sustained by π-hole driven pnictogen bonds hosted by nitrogen. To understand the effect of substitution on this π-hole and thus the pnictogen bond, heterodimers of nitrobenzene (NB; phenyl substitution in place of methyl) with ammonia (AM) have been probed, as a test case, using matrix isolation infrared spectroscopy and ab initio computations. Of the four structures optimized on the potential energy surface the energetically dominant global minimum, stabilized by π-hole driven O=N←N pnictogen bonding with co-operative N-H←O hydrogen bonding, was experimentally identified at low temperatures. A comparison of the pnictogen bonding of NB-AM dimers with NM counterpart (NM-AM dimers) divulged the dominance of electrostatic origin of pnictogen bonding in both the class of dimers. The reduced strength of pnictogen bonding in NB-AM dimers in comparison to NM-AM dimers was discerned, which has been established to be a consequence of the reduced electrostatic potential at the π-hole of NB relative to that in NM. The strength of π-hole driven pnictogen bond was directly correlated with the binding energy and the infrared shifts in the signature vibrational bands of the NB, NM and AM submolecules due to dimerization under matrix isolated conditions at low temperatures., (© 2023 Wiley-VCH GmbH.)

Proper regulation of the bacterial cell envelope is critical for cell survival. Identification and characterization of enzymes that maintain cell envelope homeostasis is crucial, as they can be targets for effective antibiotics. In this study, we have identified a novel enzyme, called EstG, whose activity protects cells from a variety of lethal assaults in the ⍺-proteobacterium Caulobacter crescentus. Despite homology to transpeptidase family cell wall enzymes and an ability to protect against cell-wall-targeting antibiotics, EstG does not demonstrate biochemical activity toward cell wall substrates. Instead, EstG is genetically connected to the periplasmic enzymes OpgH and BglX, responsible for synthesis and hydrolysis of osmoregulated periplasmic glucans (OPGs), respectively. The crystal structure of EstG revealed similarities to esterases and transesterases, and we demonstrated esterase activity of EstG in vitro. Using biochemical fractionation, we identified a cyclic hexamer of glucose as a likely substrate of EstG. This molecule is the first OPG described in Caulobacter and establishes a novel class of OPGs, the regulation and modification of which are important for stress survival and adaptation to fluctuating environments. Our data indicate that EstG, BglX, and OpgH comprise a previously unknown OPG pathway in Caulobacter. Ultimately, we propose that EstG is a novel enzyme that instead of acting on the cell wall, acts on cyclic OPGs to provide resistance to a variety of cellular stresses., Competing Interests: Declaration of interests S.B.G. is a founder of and holds equity in AMS, LLC and is or was a consultant to Genesis Therapeutics, XinThera, and Scorpion Therapeutics., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The existence of unique ON⋯π pnicogen bonding in combination with C-H⋯π/C-H⋯O hydrogen bonding interactions has been experimentally affirmed in the heterodimers of nitromethane with aliphatic (acetylene; NMAc) and aromatic (benzene; NMBz) π-electron donors at low temperatures under isolated conditions. The potential energy surfaces of NMAc and NMBz dimers have been probed for stationary points using ab initio and DFT computational methods. Three unique geometries for NMAc dimers were optimized, which were stabilized through mixed ON⋯π pnicogen bonding and C-H⋯π/C-H⋯O hydrogen bonding interactions with varying strength. Within the Ar matrix at 12 K, only the C-H⋯π and C-H⋯O bound NMAc dimer was generated, while in N 2 , two geometries, one stabilized by pnicogen bonded ON⋯π and C-H⋯π interactions and the other by C-H⋯π and C-H⋯O interactions, were produced. The NMBz dimer has only one structure stabilized by both ON⋯π pnicogen and C-H⋯π hydrogen bonding interactions that appears to be generated preferentially. The binding energies of both the dimers have the greatest contribution from electrostatics in both classes of NMAc and NMBz dimers, which is closely followed by dispersion forces in the case of NMBz. The increased proton affinity of benzene over acetylene appears to enhance the strength of C-H⋯π hydrogen bonds in NMBz while the ON⋯π pnicogen bonds remain quite similar in strength in both NMBz and NMAc dimers.

Background: Poor communication and lack of standardized handover practices contribute to adverse events. Intensive care organizations recommend standardized, structured written and verbal handover., Objectives: Investigate the effectiveness of, and barriers to, Intensive Care Unit (ICU) patient handover at ward transfer. Screen for patient safety incidents related to poor handover and improve practice where deficiencies are identified., Methods: A survey of ward doctors about specific ICU to ward transfers and online surveys ascertaining opinions of handover processes were sent to ward-based and ICU doctors at a large, adult, university affiliated, Australian quaternary hospital. We delivered departmental education and created then publicized a new electronic ICU transfer summary. The summary included a mandatory tick-box to confirm verbal handover completion. Surveys re-assessing practice were then performed., Results: Forty ward-based doctors were surveyed about specific transfers, with 7 (18%) instances of issues related to handover identified. Eighty-seven ward doctors completed the pre-interventions survey; 48 (55%) were aware of the existing written transfer summary. Post-interventions, 47 (75%) of 63 ward doctor responders were aware of it (p < 0.05). Pre-interventions, 14 (16%) ward doctors rated ICU handovers as excellent or good, rising to 21 (34%) post-interventions (p < 0.05). Thirty-nine ICU doctors completed the pre-interventions survey; 5 (13%) rated ICU to ward handover as excellent or good, rising to 9 (35%) when re-surveyed (p = 0.097)., Conclusions: The perceived quality of ICU to ward handover improved after our interventions. However, ICU doctors continue to transfer patients without verbally handing over, with contacting the ward team representing a significant handover barrier.

Both tetrel and pnicogen bonds are known to be induced through σ-/π-holes. This work reports computational and experimental evidence of the carbonyl carbon of acetone hosting a tetrel bond by dispersion rather electrostatic forces, for the first time, while phosphorus of POCl 3 sustains pnicogen bonding via the σ-hole. Heterodimers of POCl 3 with acetone (CH 3 COCH 3 ) have been isolated within inert gas matrixes of Ar and N 2 at 12 K. Characteristic vibrational bands at P═O stretching of POCl 3 and C═O stretching of CH 3 COCH 3 have been obtained in support of the computations. The potential energy surface has been traced computationally using ab initio and density functional methods. CH 3 COCH 3 harboring such a tetrel bond, in itself, is quite intriguing. The interplay of these interactions has been comprehended by the quantum theory of atoms in molecules, natural bond orbital, energy decomposition, electrostatic potential mapping, and noncovalent interaction analyses.

Complex formation between uranyl and carboxylate ligands (benzoate, nicotinate and isonicotinate) has been studied extensively by absorption and luminescence spectroscopy in acetonitrile medium. Experimental data had indicated the existence of stable and enhanced luminescent tris(carboxylato) uranyl(VI) complexes i.e. [UO 2 (L) 3 ] - with D 3h symmetry. The high luminescence of these complexes was due to the sensitization of the O yl → U ligand to metal charge transfer (LMCT) emission by extremely intense equatorial (carboxylate ligands) LMCT bands. The variation in the experimentally observed parameters such as intensity of equatorial LMCT bands, luminescence lifetimes, quantum yields and structural parameters among tris(carboxylato) uranyl(VI) complexes are affirmed by quantum chemical calculations using density functional theory and the computational results are found to be in good agreement with experimental findings. Interestingly, in a very dilute mixture of [UO 2 (L) 3 ] - and Eu(III), energy transfer from uranyl to Eu(III) is observed and it leads to the detection of europium at trace levels. This is an intriguing observation as none of the previous studies have reported such a low level of detection limit of Eu(III) by means of energy transfer from any metal.

Geometries of nitromethane homodimers have been revisited using ab initio and density functional methodologies, following their formation within cryogenic matrices, confirmed using infrared spectroscopy. In contrast to the claim that the intermolecular interactions are due to dispersion forces or very weak hydrogen bonds, in the present work, concrete evidence for the prevalence of O═N...O pnicogen bonding has been presented. The pnicogen bonds have been found to be primarily responsible for the characteristic geometry of a homodimer. The formation of a nitromethane dimer with pnicogen bonding stabilization is evidenced using matrix isolation infrared spectroscopy with Ne and Ar matrices and computations. The interactions within homodimers have been characterized using quantum theory of atoms in molecules, natural bond orbital, energy decomposition, electrostatic potential mapping, and noncovalent interaction analyses. The larger intermolecular separations in liquid nitromethane indicated by previous molecular dynamics-based studies alongside the supposed invariance of infrared spectra in the gas phase and liquid phase could have led to the assumption of a lack of intermolecular interactions. However, the prevalence of hydrogen and pnicogen bonds across these larger than usual separations is affirmed by the geometries presented here.

Purpose: Up to 30% of spine facet osteoarthritis patients with lumbar spinal stenosis (SF-OA ​+ ​LSS) have little to no improvement in their pain after surgery. Lack of meaningful improvement in pain following surgery provides a unique opportunity to identify specific predictive biomarker signatures that might be associated with the outcomes of surgical treatment. The objective of the present study was to determine whether a microRNA (miRNA) biomarker signature could be identified in presurgical blood plasma that corresponded with levels of SF-OA ​+ ​LSS patient post-surgical pain intensity one year later., Methods: RNA was extracted from baseline plasma of SF-OA ​+ ​LSS patients and prepared for miRNA sequencing. Statistical approaches were performed to identify differentially expressed miRNAs associated with reduced 1-year postsurgical pain (n ​= ​56). Using an integrated computational approach, we further created predicted gene and pathway networks for each identified miRNA., Results: We identified a panel of 4 circulating candidate miRNAs (hsa-miR-155-5p, hsa-let-7e-5p, hsa-miR-125a-5p, hsa-miR-99b-5p) with higher levels at presurgical baseline that were associated with greater changes in % NPRS20Δ, reflecting reduced pain intensity levels at one year. Genes encoding hsa-let-7e-5p, hsa-miR-125a-5p, and hsa-miR-99b-5p are part of an evolutionarily conserved miRNA cluster. Using integrated computational analyses, we showed that mammalian target of rapamycin, transforming growth factor-β1 receptor, Wnt signaling, epithelial-mesenchymal transition regulators, and cholecystokinin signaling were enriched pathways of predicted gene targets., Conclusions: Taken together, our findings suggest that 4 presurgical baseline circulating miRNAs correlate with 1-year postsurgical SF-OA ​+ ​LSS patient pain intensity and represent possible candidate biomarker signature of surgical pain response., Competing Interests: All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript., (© 2022 The Authors.)

Eukaryotes segregate their chromosomes during mitosis and meiosis by attaching chromosomes to the microtubules of the spindle so that they can be distributed into daughter cells. The complexity of centromeres ranges from the point centromeres of yeast that attach to a single microtubule to the more complex regional centromeres found in many metazoans or holocentric centromeres of some nematodes, arthropods and plants, that bind to dozens of microtubules per kinetochore. In vertebrates, the centromere is defined by a centromere specific histone variant termed Centromere Protein A (CENP-A) that replaces histone H3 in a subset of centromeric nucleosomes. These CENP-A nucleosomes are distributed on long stretches of highly repetitive DNA and interspersed with histone H3 containing nucleosomes. The mechanisms by which cells control the number and position of CENP-A nucleosomes is unknown but likely important for the organization of centromeric chromatin in mitosis so that the kinetochore is properly oriented for microtubule capture. CENP-A chromatin is epigenetically determined thus cells must correct errors in CENP-A organization to prevent centromere dysfunction and chromosome loss. Recent improvements in sequencing complex centromeres have paved the way for defining the organization of CENP-A nucleosomes in centromeres. Here we discuss the importance and challenges in understanding CENP-A organization and highlight new discoveries and advances enabled by recent improvements in the human genome assembly., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sundararajan and Straight.)

Objective: To evaluate a stratified screening process for the early identification of axial spondyloarthritis (SpA) with consideration of the following: 1) wait times from primary care to rheumatology screen, 2) incremental precision and accuracy from primary care to rheumatology screening, and 3) diagnostic delay., Methods: Adults with low back pain attending primary care at low back pain clinics prospectively underwent a primary standardized clinical screening. Patients with low back pain of >3 months who experienced symptom onset at age <50 years were referred for a comprehensive secondary screening by a physical therapist with advanced rheumatology training. At secondary screening, patients with features of inflammation were classified as being at a low, medium, or high risk for axial SpA versus no risk for axial SpA. Precision and accuracy of this screening strata were measured against a rheumatologist with expertise in axial SpA., Results: Overall, 405 patients underwent primary and secondary screening in the present study. The study cohort had a mean ± SD age of 36.9 ± 9.9 years, and 55% were women. HLA-B27 was present in 14.4% of patients. Median wait time from primary screening to secondary screening was 15 days. Axial SpA risk assignment by rheumatologist was 64.9% for no risk or low risk for axial SpA and 35.1% for medium risk or high risk for axial SpA. The best combination of sensitivity (68%), specificity (90%), positive predictive values (80%), and negative predictive values (84%) was evident in the secondary screening. In this cohort, 15.6% of patients received a final diagnosis of axial SpA. Median low back pain duration from symptom onset to diagnosis was 2 years for nonradiographic axial SpA and 7 years for ankylosing spondylitis., Conclusion: A stratified interprofessional screening process can facilitate rapid diagnosis of persistent low back pain with high precision and accuracy in patients who have axial SpA., (© 2021 American College of Rheumatology.)

Studies of genome regulation routinely use high-throughput DNA sequencing approaches to determine where specific proteins interact with DNA, and they rely on DNA amplification and short-read sequencing, limiting their quantitative application in complex genomic regions. To address these limitations, we developed directed methylation with long-read sequencing (DiMeLo-seq), which uses antibody-tethered enzymes to methylate DNA near a target protein's binding sites in situ. These exogenous methylation marks are then detected simultaneously with endogenous CpG methylation on unamplified DNA using long-read, single-molecule sequencing technologies. We optimized and benchmarked DiMeLo-seq by mapping chromatin-binding proteins and histone modifications across the human genome. Furthermore, we identified where centromere protein A localizes within highly repetitive regions that were unmappable with short sequencing reads, and we estimated the density of centromere protein A molecules along single chromatin fibers. DiMeLo-seq is a versatile method that provides multimodal, genome-wide information for investigating protein-DNA interactions., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

In the estimation of Zr using the ultraviolet-visible (UV-Vis) spectrophotometric technique, fluoride interference is a decade-old unsolved problem. The process of repeated fuming with strong acids is often used to remove fluoride from the solution in order to estimate Zr using spectrophotometry analysis. For the first time, in this work, a simple use of AlCl 3 is reported as a suppressing reagent to eliminate the interference of fluoride in the estimation of Zr. Xylenol orange in HCl medium is used as a complexing reagent. Linearity in the datum acquired from absorbance at 551 nm (λ max ) is achieved over the concentration range 0.25-4.5 µg mL -1 of Zr with a molar absorptivity of 35030 L·mol -1 ·cm -1 and Sandell's sensitivity of 0.003 µg·cm -2 . Zr is quantified in the variety of U-Zr alloys and various water samples using spectrophotometric detection with a classical univariate calibration with suppressing of fluoride interference through AlCl 3 . Results from this novel analytical method herein developed for the first time are compared with those achieved from gravimetric analysis.

The histone variant CENP-A is the epigenetic determinant for the centromere, where it is interspersed with canonical H3 to form a specialized chromatin structure that nucleates the kinetochore. How nucleosomes at the centromere arrange into higher order structures is unknown. Here we demonstrate that the human CENP-A-interacting protein CENP-N promotes the stacking of CENP-A-containing mononucleosomes and nucleosomal arrays through a previously undefined interaction between the α6 helix of CENP-N with the DNA of a neighboring nucleosome. We describe the cryo-EM structures and biophysical characterization of such CENP-N-mediated nucleosome stacks and nucleosomal arrays and demonstrate that this interaction is responsible for the formation of densely packed chromatin at the centromere in the cell. Our results provide first evidence that CENP-A, together with CENP-N, promotes specific chromatin higher order structure at the centromere., (© 2022. The Author(s).)

Objectives: This study was conducted to explore the perspectives and opinions of intensive care unit (ICU) nurses and doctors at a COVID-19-designated pandemic hospital concerning the preparedness and response to COVID-19 and to consolidate the lessons learnt for crisis/disaster management in the future., Design: A qualitative study using in-depth interviews (IDIs) and focus group discussions (FGDs). Purposeful sampling was conducted to identify participants. A semistructured guide was used to facilitate IDIs with individual participants. Two FGDs were conducted, one with the ICU doctors and another with the ICU nurses. Thematic analysis identified themes and subthemes informing about the level of preparedness, response measures, processes, and factors that were either facilitators or those that triggered challenges., Setting: ICU in a quaternary referral centre affiliated to a university teaching COVID-19-designated pandemic hospital, in Adelaide, South Australia., Participants: The participants included eight ICU doctors and eight ICU nurses for the IDIs. Another 16 clinicians participated in FGDs., Results: The study identified six themes relevant to preparedness for, and responses to, COVID-19. The themes included: (1) staff competence and planning, (2) information transfer and communication, (3) education and skills for the safe use of personal protective equipment, (4) team dynamics and clinical practice, (5) leadership, and (6) managing end-of-life situations and expectations of caregivers., Conclusion: Findings highlight that preparedness and response to the COVID-19 crisis were proportionate to the situation's gravity. More enablers than barriers were identified. However, opportunities for improvement were recognised in the domains of planning, logistics, self-sufficiency with equipment, operational and strategic oversight, communication and managing end-of-life care., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Neurosyphilis is an infection caused by the spirochete Treponema pallidum, which causes infiltration and thickening of brain meninges. Despite being an Old World disease, the rates of infection continue to rise. This clinical challenge involves early and accurate diagnosis, as neurosyphilis masquerades with various clinical symptoms and is often missed during initial presentation to the hospital. A comprehensive history and clinical examination are essential to detect suspicious cases early for further cerebrospinal fluid examination and neuroimaging. Patients treated with benzylpenicillin for a specific duration often show promising clinical and cognitive improvement, thus emphasizing the need for constant vigilance in our day-to-day practice., Case Presentation: A 77-year-old Caucasian gentleman presented to our hospital repeatedly with multiple episodes of presyncope and cognitive impairment. He also demonstrated bilateral deafness, tabes dorsalis, and left sixth cranial nerve palsy. His cerebrospinal fluid examination showed a nonreactive venereal disease research laboratory test, and magnetic resonance imaging of the brain revealed a gumma., Conclusion: The diagnosis of neurosyphilis in the elderly requires a combination of clinical vigilance and a high index of suspicion, along with multimodal investigations, including cerebrospinal fluid examination and brain imaging., (© 2021. The Author(s).)

This paper aims to evaluate the performance of multiple non-linear regression techniques, such as support-vector regression (SVR), k-nearest neighbor (KNN), Random Forest Regressor, Gradient Boosting, and XGBOOST for COVID-19 reproduction rate prediction and to study the impact of feature selection algorithms and hyperparameter tuning on prediction. Sixteen features (for example, Total&#95;cases&#95;per&#95;million and Total&#95;deaths&#95;per&#95;million) related to significant factors, such as testing, death, positivity rate, active cases, stringency index, and population density are considered for the COVID-19 reproduction rate prediction. These 16 features are ranked using Random Forest, Gradient Boosting, and XGBOOST feature selection algorithms. Seven features are selected from the 16 features according to the ranks assigned by most of the above mentioned feature-selection algorithms. Predictions by historical statistical models are based solely on the predicted feature and the assumption that future instances resemble past occurrences. However, techniques, such as Random Forest, XGBOOST, Gradient Boosting, KNN, and SVR considered the influence of other significant features for predicting the result. The performance of reproduction rate prediction is measured by mean absolute error (MAE), mean squared error (MSE), root mean squared error (RMSE), R-Squared, relative absolute error (RAE), and root relative squared error (RRSE) metrics. The performances of algorithms with and without feature selection are similar, but a remarkable difference is seen with hyperparameter tuning. The results suggest that the reproduction rate is highly dependent on many features, and the prediction should not be based solely upon past values. In the case without hyperparameter tuning, the minimum value of RAE is 0.117315935 with feature selection and 0.0968989 without feature selection, respectively. The KNN attains a low MAE value of 0.0008 and performs well without feature selection and with hyperparameter tuning. The results show that predictions performed using all features and hyperparameter tuning is more accurate than predictions performed using selected features., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kaliappan, Srinivasan, Mian Qaisar, Sundararajan, Chang and C.)

Introduction: Diversion of prescription opioid medication is a contributor to the opioid epidemic. Safe handling practices can reduce the risk of diversion. We aimed to understand: 1) if orthopaedic patients received instructions on how to safely handle opioids, 2) their typical storage/disposal practices, and 3) their willingness to participate in an opioid disposal program (ODP)., Methods: Cross-sectional study of adult orthopaedic patients who completed an anonymous survey on current or past prescription opioid use, instruction on handling, storage and disposal practices, presence of children in the household, and willingness to participate in an ODP. Frequencies and percentages of responses were computed, both overall and stratified by possession of unused opioids., Results: 569 respondents who reported either current or past prescription opioid use were analyzed. 44% reported receiving storage instructions and 56% reported receiving disposal instructions from a health care provider. Many respondents indicated unsafe handling practices: possessing unused opioids (34%), using unsafe storage methods (90%), and using unsafe disposal methods (34%). Respondents with unused opioids were less likely to report receiving handling instructions or using safe handling methods, and 47% of this group reported having minors or young adults in the household. Respondents who received storage and disposal instructions were more likely to report safe storage and disposal methods. Seventy-four percent of respondents reported that they would participate in an ODP., Conclusion: While many orthopaedic patients report inadequate education on safe opioid handling and using unsafe handling practices, findings suggest targeted education is associated with better behaviours. However, patients are willing to safely dispose of unused medication if provided a convenient option. These findings suggest a need to address patient knowledge and behavior regarding opioid handling to reduce the risk of opioid diversion., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Y. Raja Rampersaud has received royalties from Medtronic and holds investments in Arthur Health Corporation. This does not alter our adherence to PLOS ONE policies on sharing data and materials. All other co-authors have no competing interests to report.

A new method using Nd(III) absorption peak as a probe is described for the measurement of nitric acid concentration in aqueous solution. The hypersensitive peak of Nd(III) at 575.1 nm shows a substantial enhancement in the absorbance in comparison to other absorption peaks with increasing nitric acid concentration. The integrated area and absorbance of this hypersensitive peak show a linear dependency over a large dynamic range of 0.5-15.5 M of nitric acid. A methodology for the correction of spectral interference to the probing absorption peak of Nd(III) is also reported. The method is applied for the measurement of nitric acid in synthetic high level liquid waste solution and shown to be comparable to that obtained by titrimetric method. The present method can be easily adopted for the measurement of nitric acid concentration in aqueous raffinate solutions of nuclear reprocessing streams., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Centromeres play an essential function in cell division by specifying the site of kinetochore formation on each chromosome for mitotic spindle attachment. Centromeres are defined epigenetically by the histone H3 variant Centromere Protein A (Cenpa). Cenpa nucleosomes maintain the centromere by designating the site for new Cenpa assembly after dilution by replication. Vertebrate centromeres assemble on tandem arrays of repetitive sequences, but the function of repeat DNA in centromere formation has been challenging to dissect due to the difficulty in manipulating centromeres in cells. Xenopus laevis egg extracts assemble centromeres in vitro, providing a system for studying centromeric DNA functions. However, centromeric sequences in Xenopus laevis have not been extensively characterized. In this study, we combine Cenpa ChIP-seq with a k -mer based analysis approach to identify the Xenopus laevis centromere repeat sequences. By in situ hybridization, we show that Xenopus laevis centromeres contain diverse repeat sequences, and we map the centromere position on each Xenopus laevis chromosome using the distribution of centromere-enriched k -mers. Our identification of Xenopus laevis centromere sequences enables previously unapproachable centromere genomic studies. Our approach should be broadly applicable for the analysis of centromere and other repetitive sequences in any organism., (© 2021 Smith et al.; Published by Cold Spring Harbor Laboratory Press.)

Background: Interest in postoperative healthcare utilization has increased following the implementation of episode-of-care funding for elective orthopedic surgery. Most efforts have focused on readmission; however, little has been reported on emergency department (ED) presentation. We analyzed elective, primary total hip or knee arthroplasty (THA and TKA) cases to determine the rate, reasons, risk factors, timing, and hospital cost associated with 30-day ED presentations., Methods: An observational study of patients who underwent primary, elective TKA and THA between January 1, 2016, and December 31, 2017, was performed. The primary outcome was an ED visit within 30-days of the index operation. Secondary outcomes included reasons, risk factors, timing, and hospital cost of ED visits. A multivariable logistic regression was undertaken to determine patient factors associated with ED presentation., Results: Overall, 1690 patients were included, of which 9.2% presented to the ED within 30-days of surgery. Approximately two-thirds of the visits were after-hours, and most were discharged home without readmission (81.4%). The most commonly reported reasons were wound concerns (30.1%) and pain (20.5%). Older age (OR 1.1, P = .03) and preoperative dyspnea (OR 2.1, P < .001) increased the odds of ED visits. The mean cost of an ED visit was significantly greater after-hours (P = .015)., Conclusion: Overall, 1 in 10 patients undergoing TKA/THA presented to the ED within 30-days of surgery, of which over 80% were not readmitted, and most occurred after-hours where cost is greatest. Our observations suggest ED visits following TKA/THA are common, and most are likely preventable. Future efforts should focus on developing interventions to reduce these visits., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The role of nitrogen, the first member of the pnicogen group, as an electron donor in hypervalent non-covalent interactions has been established long ago, while observation of its electron accepting capability is still elusive experimentally, and remains quite intriguing, conceptually. In the light of minimal computational exploration of this novel class of pnicogen bonding so far, the present work provides experimental proof with unprecedented clarity, for the existence of N(acceptor)N(donor) interaction using the model nitromethane (NM) molecule with ammonia (AM) as a Lewis base in NM-AM aggregates. The NM-AM dimer, in which the nitrogen atom of NM (as a unique pnicogen) accepts electrons from AM (the traditional electron donor), was synthesized at low temperatures under isolated conditions within inert gas matrixes and was characterized using infrared spectroscopy. The experimental generation of the NM-AM dimer stabilized via NN interaction has strong corroboration from ab initio calculations. Furthermore, confirmation regarding the directional prevalence of this NN interaction over C-HN and N-HO hydrogen bonding is elucidated quantitatively by quantum theory of atoms in molecules (QTAIM), electrostatic potential mapping (ESP), natural bond orbital (NBO), non-covalent interaction (NCI) and energy decomposition (ED) analyses. The present study also allows the extension of σ-hole/π-hole driven interactions to the atoms of the second period, in spite of their low polarizability.

Background: Coronavirus disease 2019 (COVID-19) pandemic has caused unprecedented pressure on healthcare system globally. Lack of high-quality evidence on the respiratory management of COVID-19-related acute respiratory failure (C-ARF) has resulted in wide variation in clinical practice., Methods: Using a Delphi process, an international panel of 39 experts developed clinical practice statements on the respiratory management of C-ARF in areas where evidence is absent or limited. Agreement was defined as achieved when > 70% experts voted for a given option on the Likert scale statement or > 80% voted for a particular option in multiple-choice questions. Stability was assessed between the two concluding rounds for each statement, using the non-parametric Chi-square (χ 2 ) test (p < 0·05 was considered as unstable)., Results: Agreement was achieved for 27 (73%) management strategies which were then used to develop expert clinical practice statements. Experts agreed that COVID-19-related acute respiratory distress syndrome (ARDS) is clinically similar to other forms of ARDS. The Delphi process yielded strong suggestions for use of systemic corticosteroids for critical COVID-19; awake self-proning to improve oxygenation and high flow nasal oxygen to potentially reduce tracheal intubation; non-invasive ventilation for patients with mixed hypoxemic-hypercapnic respiratory failure; tracheal intubation for poor mentation, hemodynamic instability or severe hypoxemia; closed suction systems; lung protective ventilation; prone ventilation (for 16-24 h per day) to improve oxygenation; neuromuscular blocking agents for patient-ventilator dyssynchrony; avoiding delay in extubation for the risk of reintubation; and similar timing of tracheostomy as in non-COVID-19 patients. There was no agreement on positive end expiratory pressure titration or the choice of personal protective equipment., Conclusion: Using a Delphi method, an agreement among experts was reached for 27 statements from which 20 expert clinical practice statements were derived on the respiratory management of C-ARF, addressing important decisions for patient management in areas where evidence is either absent or limited., Trial Registration: The study was registered with Clinical trials.gov Identifier: NCT04534569.

Objectives: To investigate the role of zinc finger protein 440 (ZNF440) in the pathophysiology of cartilage degeneration during facet joint (FJ) and knee osteoarthritis (OA)., Methods: Expression of ZNF440 in FJ and knee cartilage was determined by immunohistochemistry, quantitative (q)PCR, and Western blotting (WB). Human chondrocytes isolated from FJ and knee OA cartilage were cultured and transduced with ZNF440 or control plasmid, or transfected with ZNF440 or control small interfering RNA (siRNA), with/without interleukin (IL)-1β. Gene and protein levels of catabolic, anabolic and apoptosis markers were determined by qPCR or WB, respectively. In silico analyses were performed to determine compounds with potential to inhibit expression of ZNF440., Results: ZNF440 expression was increased in both FJ and knee OA cartilage compared to control cartilage. In vitro, overexpression of ZNF440 significantly increased expression of MMP13 and PARP p85, and decreased expression of COL2A1. Knockdown of ZNF440 with siRNA partially reversed the catabolic and cell death phenotype of human knee and FJ OA chondrocytes stimulated with IL-1β. In silico analysis followed by validation assays identified scriptaid as a compound with potential to downregulate the expression of ZNF440. Validation experiments showed that scriptaid reduced the expression of ZNF440 in OA chondrocytes and concomitantly reduced the expression of MMP13 and PARP p85 in human knee OA chondrocytes overexpressing ZNF440., Conclusions: The expression of ZNF440 is significantly increased in human FJ and knee OA cartilage and may regulate cartilage degenerative mechanisms. Furthermore, scriptaid reduces the expression of ZNF440 and inhibits its destructive effects in OA chondrocytes., (Copyright © 2020 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Accurate and low-cost sleep measurement tools are needed in both clinical and epidemiological research. To this end, wearable accelerometers are widely used as they are both low in price and provide reasonably accurate estimates of movement. Techniques to classify sleep from the high-resolution accelerometer data primarily rely on heuristic algorithms. In this paper, we explore the potential of detecting sleep using Random forests. Models were trained using data from three different studies where 134 adult participants (70 with sleep disorder and 64 good healthy sleepers) wore an accelerometer on their wrist during a one-night polysomnography recording in the clinic. The Random forests were able to distinguish sleep-wake states with an F1 score of 73.93% on a previously unseen test set of 24 participants. Detecting when the accelerometer is not worn was also successful using machine learning ([Formula: see text]), and when combined with our sleep detection models on day-time data provide a sleep estimate that is correlated with self-reported habitual nap behaviour ([Formula: see text]). These Random forest models have been made open-source to aid further research. In line with literature, sleep stage classification turned out to be difficult using only accelerometer data.

The branching of a methyl group in a linear chain has a profound influence on the conformational morphology as it wields a strong control in reducing a large number of conformations. To unravel the effect of branching on the second non-hyperconjugative carbon atom on the conformational landscape, the conformations of tris(2-methylbutyl)phosphate (T2MBP) were studied using Density Functional Theory (DFT) computations and matrix isolation infrared spectroscopy. Experimentally, T2MBP along with N 2 /Ar/Kr/Xe gases was effusively expanded and deposited at a low temperature of 12 K, which was subsequently probed using infrared spectroscopy. The computations of all the conformations were accomplished using the B3LYP level of theory with the 6-311++G(d,p) basis set. A dimethyl(2-methylbutyl) phosphate (DM2MBP) prototype, a molecule containing a single 2-methylbutyl moiety, was examined for its conformations. Computations predicted 18 and 9 conformations each for the 'gauche' and 'trans' families, respectively, in which the third branched carbon completely influences the orientation of the fourth carbon, which simplifies the conformational problem of DM2MBP. Of the 18 and 9 bunches each in the 'gauche' and 'trans' families, only 7 and 3 conformations, respectively, became energetically important, which when extrapolated to T2MBP resulted in 343 and 147 conformational possibilities. The factor of degeneracy further reduced these numbers and a total of 168 conformations effectively contribute to the conformational composition of T2MBP in the gas phase. The role of stereo electronic and steric factors prevalent in the conformational clusters of T2MBP was unravelled respectively using natural bond orbital and non-covalent interaction analyses.

Heterodimers of POCl 3 -CHCl 3 were generated in Ne, Ar, and Kr matrixes at low temperatures and were studied using infrared spectroscopy. The remarkable role of co-operative pentavalent phosphorus bonding in the stabilization of the structure dictated by hydrogen bonding is deciphered. The complete potential energy surface of the heterodimer was scanned by ab initio and density functional theory computational methodologies. The hydrogen bond between the phosphoryl oxygen of POCl 3 and C-H group of CHCl 3 in heterodimers induces a blue-shift in the C-H stretching frequency within the Ne matrix. However, in Ar and Kr matrixes, the C-H stretching frequency is exceptionally red-shifted in stark contrast with Ne. The plausibility of the Fermi resonance by the C-H stretching vibrational mode with higher order modes in the heterodimers has been eliminated as a possible cause within Ar and Kr matrixes by isotopic substitution (CDCl 3 ) experiments. To evaluate the influence of matrixes as a possible cause of red-shift, self-consistent Iso-density polarized continuum reaction field model was applied. This conveyed the important role of the dielectric matrixes in inducing the fascinating vibrational shift from blue (Ne) to red (Ar and Kr) due to the matrix specific transmutation of the POCl 3 -CHCl 3 structure. The heterodimer produced in the Ne matrix possesses a cyclic structure stabilized by hydrogen bonding with co-operative phosphorus bonding, while in Ar and Kr the generation of an acyclic open structure stabilized solely by hydrogen bonding is promoted. Compelling justification regarding the dispersion force based influence of matrix environments in addition to the well-known dielectric influence is presented.

Albeit the first account of hypervalentπ interactions has been reported with halogenπ interactions, the feasibility of their extension to other hypervalent atoms as possible Lewis acids is still open. In this work, the role of phosphorus as an acceptor from the π electron cloud (Pπ pnicogen or phosphorus bonding) in PCl3-C2H2 and PCl3-C2H4 heterodimers is explored, by combining matrix isolation infrared spectroscopy with ab initio and DFT computational methodologies. The respective potential energy surfaces of the PCl3-C2H2 and PCl3-C2H4 heterodimers reveal unique minima stabilized by a concert of reasonably strong to weak interactions, of which Pπ phosphorus bonding was energetically dominant. Heterodimers, trimers and tetramers bound primarily by this unique phosphorus bond were generated at low temperatures. The dominance of phosphorus bonding in the PCl3-C2H2 and PCl3-C2H4 heterodimers over other interactions (such as Hπ, HCl, HP, Clπ and lone pair-π interactions) was confirmed and substantiated using extended quantum theory of atoms in molecules, natural bond orbital, electrostatic potential mapping and energy decomposition analyses. The following inferences in correlation with results from non-covalent-interaction analysis offer a complete understanding of the nature of the Pπ phosphorus bonding interactions. The significance of electrostatic forces kinetically favoring the formation of phosphorus bonded heterodimers, in addition to thermodynamic stabilization, is demonstrated experimentally.

The scale of the COVID-19 pandemic represents unprecedented challenges to healthcare systems. We describe a cohort of 18 critically ill COVID-19 patients - to our knowledge the highest number, in a single intensive care unit in Australia. We discuss the complex challenges and dynamic solutions that concern an intensive care unit pandemic response. Acting as the State's COVID-19 referral hospital, we provide local insights to consider alongside national guidelines., (© 2020 Royal Australasian College of Physicians.)

Bacterial cell division requires the assembly of a multiprotein division machinery, or divisome, that remodels the cell envelope to cause constriction. The cytoskeletal protein FtsZ forms a ringlike scaffold for the divisome at the incipient division site. FtsZ has three major regions: a conserved GTPase domain that polymerizes into protofilaments on binding GTP, a C-terminal conserved peptide (CTC) required for binding membrane-anchoring proteins, and a C-terminal linker (CTL) region of varied length and low sequence conservation. Recently, we demonstrated that the CTL regulates FtsZ polymerization properties in vitro and Z-ring structure and cell wall metabolism in vivo In Caulobacter crescentus , an FtsZ variant lacking the CTL (designated ΔCTL) can recruit all known divisome members and drive local cell wall synthesis but has dominant lethal effects on cell wall metabolism. To understand the underlying mechanism of the CTL-dependent regulation of cell wall metabolism, we expressed chimeras of FtsZ domains from C. crescentus and Escherichia coli and observed that the E. coli GTPase domain fused to the C. crescentus CTC phenocopies C. crescentus ΔCTL. By investigating the contributions of FtsZ-binding partners, we identified variants of FtsA, a known membrane anchor for FtsZ, that delay or exacerbate the ΔCTL phenotype. Additionally, we observed that the ΔCTL protein forms extended helical structures in vivo upon FtsA overproduction. We propose that misregulation downstream of defective ΔCTL assembly is propagated through the interaction between the CTC and FtsA. Overall, our study provides mechanistic insights into the CTL-dependent regulation of cell wall enzymes downstream of FtsZ polymerization. IMPORTANCE Bacterial cell division is essential and requires the recruitment and regulation of a complex network of proteins needed to initiate and guide constriction and cytokinesis. FtsZ serves as a master regulator for this process, and its function is highly dependent on both its assembly into the canonical Z ring and interactions with protein binding partners, all of which results in the activation of enzymes that remodel the cell wall to drive constriction. Using mutants of FtsZ, we have elaborated on the role of its C-terminal linker domain in regulating Z-ring stability and dynamics, as well as the requirement for its conserved C-terminal domain and interaction with the membrane-anchoring protein FtsA for regulating the process of cell wall remodeling for constriction., (Copyright © 2020 American Society for Microbiology.)

Sentimental analysis aims at inferring how people express their opinion over any piece of text or topic of interest. This article deals with detection of an implicit form of the sentiment, referred to as sarcasm. Sarcasm conveys the opposite of what people try to convey in order to criticize or ridicule in a humorous way. It plays a vital role in social networks since most of the tweets or posts contain sarcastic nuances. Existing approaches towards the study of sarcasm deals only with the detection of sarcasm. In this paper, in addition to detecting sarcasm from text, an approach has been proposed to identify the type of sarcasm. The main motivation behind determining the types of sarcasm is to identify the level of hurt or the true intent behind the sarcastic text. The proposed work aims to improve upon the existing approaches by incorporating a new perspective which classifies the sarcasm based on the level of harshness employed. The major application of the proposed work would be relating the emotional state of a person to the type of sarcasm exhibited by him/her which could provide major insights about the emotional behavior of a person. An ensemble-based feature selection method has been proposed for identifying the optimal set of features needed to detect sarcasm from tweets. This optimal set of features was employed to detect whether the tweet is sarcastic or not. After detecting sarcastic sentences, a multi-rule based approach has been proposed to determine the type of sarcasm. As an initial attempt, sarcasm has been classified into four types, namely, polite sarcasm, rude sarcasm, raging sarcasm, and deadpan sarcasm. The performance and efficiency of the proposed approach has been experimentally analyzed, and change in mood of a person for each sarcastic type has been modelled. The overall accuracy of the proposed ensemble feature selection algorithm for sarcasm detection is around 92.7%, and the proposed multi-rule approach for sarcastic type identification achieves an accuracy of 95.98%, 96.20%, 99.79%, and 86.61% for polite, rude, raging, and deadpan types of sarcasm, respectively., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2020 Karthik Sundararajan and Anandhakumar Palanisamy.)

Owing to the fact that σ stacking is as important as π stacking in determining the structural motifs of aliphatic saturated cyclic hydrocarbons, in this work we have provided the first unambiguous spectroscopic evidence for the existence of σ stacking interactions in cyclohexane dimers at low temperatures. Molecular beam experiments performed using effusive nozzle and supersonic jet sources on cyclohexane in an N2 matrix generated cyclohexane dimers stabilized through σ stacking and the dimers were characterized by infrared spectroscopy. The ab initio computations carried out on cyclohexane dimers identified eclipsed (face-to-face), parallel displaced and T-shaped structures, which are predominantly stabilized by σ stacking interactions. While natural bond orbital analysis substantiated a significant amount of σ → σ* interactions involved in the stabilization, the Atoms in Molecules analysis indicated that the stacking is induced by a plausible 'dihydrogen bonding' interaction. Energy decomposition analysis disclosed that a large measure of dispersion interactions effectively contributes for the overall stability of cyclohexane dimers.

The π electron systems are the conventional electron donors to the hydrogen acceptors in hydrogen bonding. Apart from the hydrogen atom, halogens, chalcogens, pnicogens and triel/tetrel atoms can also be envisaged as electron acceptors involving π clouds. Markedly, in pnicogenπ interactions, the bonding of the hypervalent (predominantly pentavalent) state of the phosphorus atom with π electron donors is elusive and can be thought of as an intuitive extension to trivalent phosphorusπ interactions. In this work, on the one hand, POCl 3 was taken as a prototypical molecule to explore these pentavalent phosphorus interactions and on the other hand, acetylene (C 2 H 2 ), ethylene (C 2 H 4 ) and benzene (C 6 H 6 ), in which phosphorusπ bonding can be expected to compete with hydrogen and halogen bonding interactions, were taken as π electron donors. All three POCl 3 -C 2 H 2 , POCl 3 -C 2 H 4 and POCl 3 -C 6 H 6 heterodimers were experimentally generated at low temperatures in Ar and N 2 matrices and were characterized by both infrared spectroscopy and state-of-the-art quantum chemical computations. Though hydrogen bonding dominates in POCl 3 -C 2 H 2 and POCl 3 -C 2 H 4 heterodimers, phosphorus bonding plays a definite and non-trivial role in their overall stabilization. An interesting paradigm transformation was noticed in the POCl 3 -C 6 H 6 system, where pentavalent phosphorusπ bonding was observed to completely influence the hydrogen bonding interaction. To further shed light on these Pπ systems, the interaction characteristics were analyzed with the help of electrostatic potential mapping, natural bond orbital and energy decomposition analyses.