Routine Metagenomics Service for ICU Patients with Respiratory Infection.

Rationale: Respiratory metagenomics (RMg) needs evaluation in a pilot service setting to determine utility and inform implementation into routine clinical practice. Objectives: Feasibility, performance, and clinical impacts on antimicrobial prescribing and infection control were recorded during a pilot RMg service. Methods: RMg was performed on 128 samples from 87 patients with suspected lower respiratory tract infection (LRTI) on two general and one specialist respiratory ICUs at Guy's and St Thomas' NHS Foundation Trust, London. Measurements and Main Results: During the first 15 weeks, RMg provided same-day results for 110 samples (86%), with a median turnaround time of 6.7 hours (interquartile range = 6.1-7.5 h). RMg was 93% sensitive and 81% specific for clinically relevant pathogens compared with routine testing. Forty-eight percent of RMg results informed antimicrobial prescribing changes (22% escalation; 26% deescalation) with escalation based on speciation in 20 out of 24 cases and detection of acquired-resistance genes in 4 out of 24 cases. Fastidious or unexpected organisms were reported in 21 samples, including anaerobes (n = 12), Mycobacterium tuberculosis, Tropheryma whipplei, cytomegalovirus, and Legionella pneumophila ST1326, which was subsequently isolated from the bedside water outlet. Application to consecutive severe community-acquired LRTI cases identified Staphylococcus aureus (two with SCCmec and three with luk F/S virulence determinants), Streptococcus pyogenes (emm1-M1uk clone), S. dysgalactiae subspecies equisimilis (STG62647A), and Aspergillus fumigatus with multiple treatments and public health impacts. Conclusions: This pilot study illustrates the potential of RMg testing to provide benefits for antimicrobial treatment, infection control, and public health when provided in a real-world critical care setting. Multicenter studies are now required to inform future translation into routine service.

Therapy-Induced Senescence Contributes to the Efficacy of Abemaciclib in Patients with Dedifferentiated Liposarcoma.

PURPOSE: We conducted research on CDK4/6 inhibitors (CDK4/6i) simultaneously in the preclinical and clinical spaces to gain a deeper understanding of how senescence influences tumor growth in humans. PATIENTS AND METHODS: We coordinated a first-in-kind phase II clinical trial of the CDK4/6i abemaciclib for patients with progressive dedifferentiated liposarcoma (DDLS) with cellular studies interrogating the molecular basis of geroconversion. RESULTS: Thirty patients with progressing DDLS enrolled and were treated with 200 mg of abemaciclib twice daily. The median progression-free survival was 33 weeks at the time of the data lock, with 23 of 30 progression-free at 12 weeks (76.7%, two-sided 95% CI, 57.7%-90.1%). No new safety signals were identified. Concurrent preclinical work in liposarcoma cell lines identified ANGPTL4 as a necessary late regulator of geroconversion, the pathway from reversible cell-cycle exit to a stably arrested inflammation-provoking senescent cell. Using this insight, we were able to identify patients in which abemaciclib induced tumor cell senescence. Senescence correlated with increased leukocyte infiltration, primarily CD4-positive cells, within a month of therapy. However, those individuals with both senescence and increased TILs were also more likely to acquire resistance later in therapy. These suggest that combining senolytics with abemaciclib in a subset of patients may improve the duration of response. CONCLUSIONS: Abemaciclib was well tolerated and showed promising activity in DDLS. The discovery of ANGPTL4 as a late regulator of geroconversion helped to define how CDK4/6i-induced cellular senescence modulates the immune tumor microenvironment and contributes to both positive and negative clinical outcomes. See related commentary by Weiss et al., p. 649.

Case of infiltrative optic neuropathy with hypertrophic pachymeningitis as a manifestation of en plaque meningioma.

We describe a case of infiltrative optic neuropathy with hypertrophic pachymeningitis noted on MRI of the brain, presenting a diagnostic dilemma with a wide variety of differential diagnoses to consider. Our patient is a middle-aged woman with a 20-year history of migranous-sounding headaches who was incidentally found to have worsening vision in her left eye during a routine driving test visual acuity check. Neurological examination revealed a left grade III relative afferent pupillary defect and a central scotoma with red desaturation. Subsequent MRI of her brain and anterior visual pathway revealed features suggestive of an infiltrative left optic neuropathy with hypertrophic pachymeningitis. An extended workup including diagnostic lumbar puncture and blood tests for possible autoimmune, infective and neoplastic causes proved unyielding. Eventually, an endoscopic transsphenoidal biopsy helped to clinch the diagnosis of a (meningothelial subtype) WHO grade 1 meningioma as the cause of her clinical and radiological presentation.

Healthcare resilience: a meta-narrative systematic review and synthesis of reviews.

OBJECTIVES: The COVID-19 pandemic has tested global healthcare resilience. Many countries previously considered 'resilient' have performed poorly. Available organisational and system frameworks tend to be context-dependent and focus heavily on physical capacities. This study aims to explore and synthesise evidence about healthcare resilience and present a unified framework for future resilience-building. DESIGN: Systematic review and synthesis of reviews using a meta-narrative approach. SETTING: Healthcare organisations and systems. PRIMARY AND SECONDARY OUTCOME MEASURES: Definitions, concepts and measures of healthcare resilience. We used thematic analysis across included reviews to summarise evidence on healthcare resilience. RESULTS: The main paradigms within healthcare resilience include global health, disaster risk reduction, emergency management, patient safety and public health. Definitions of healthcare resilience recognise various hierarchical levels: individual (micro), facility or organisation (meso), health system (macro) and planetary or international (meta). There has been a shift from a focus on mainly disasters and crises, to an 'all-hazards' approach to resilience. Attempts to measure resilience have met with limited success. We analysed key concepts to build a framework for healthcare resilience containing pre-event, intra-event, post-event and trans-event domains. Alongside, we synthesise a definition which dovetails with our framework. CONCLUSION: Resilience increasingly takes an all-hazards approach and a process-oriented perspective. There is increasing recognition of the relational aspects of resilience. Few frameworks incorporate these, and they are difficult to capture within measurement systems. We need to understand how resilience works across hierarchical levels, and how competing priorities may affect overall resilience. Understanding these will underpin interdisciplinary, cross-sectoral and multi-level approaches to healthcare resilience for the future. PROSPERO REGISTRATION NUMBER: CRD42022314729.

Serological evaluation of risk factors for exposure to malaria in a pre-elimination setting in Malaysian Borneo.

Malaysia has reported no indigenous cases of P. falciparum and P. vivax for over 3 years. When transmission reaches such low levels, it is important to understand the individuals and locations where exposure risks are high, as they may be at greater risk in the case of a resurgence of transmission. Serology is a useful tool in low transmission settings, providing insight into exposure over longer durations than PCR or RDT. We ran blood samples from a 2015 population-based survey in northern Sabah, Malaysian Borneo on a multiplex bead assay. Using supervised machine learning methods, we characterised recent and historic exposure to Plasmodium falciparum and P. vivax and found recent exposure to P. falciparum to be very low, with exposure to both species increasing with age. We performed a risk-factor assessment on environmental, behavioural, demographic and household factors, and identified forest activity and longer travel times to healthcare as common risk-factors for exposure to P. falciparum and P. vivax. In addition, we used remote-sensing derived data and geostatistical models to assess environmental and spatial associations with exposure. We created predictive maps of exposure to recent P. falciparum in the study area and showed 3 clear foci of exposure. This study provides useful insight into the environmental, spatial and demographic risk factors for P. falciparum and P. vivax at a period of low transmission in Malaysian Borneo. The findings would be valuable in the case of resurgence of human malarias in the region.

Care for the Environment as a Consideration in Bioethics Discourse and Education.

This article argues that environmental considerations fall within the scope of medical bioethics, and there are implications specific to medical education. It endorses the need to expand the scope and epistemology of contemporary medical bioethics discourse by including themes related to environmental considerations. Our discussion begins by providing a brief history of environmental bioethics. It then offers a critique of three specific health and environmental issues, namely technology, toxics, and consumption, and discusses how these issues are key to articulating moral considerations of human health and subsequently medicine and its teaching. Lastly, it explores criticisms of including environmental issues into the bioethical debate before providing suggestions of how environmental ethics can be included into the medical curriculum. This article concludes by suggesting theoretical possibilities for environmentally inclusive bioethics, such as reorienting bioethical discussions to its original environmental advocacy and supporting environmental bioethics as a competency in medical education.

Appropriateness of lumbar spine radiography and factors influencing imaging ordering patterns: paving the path toward value-driven health care.

The demand for diagnostic imaging continues to rise. Against the backdrop of rising health care costs and finite resources, this has prompted a paradigm shift toward value-driven patient care. Inappropriate imaging is a barrier toward achieving this goal, which runs counter to prevailing evidence-based guidelines and contributes to rising healthcare costs. Our objective was to evaluate the appropriateness of lumbar spine X-rays in a tertiary referral Emergency Department (ED) and assess whether physicians' specialization and years of experience influence appropriateness. A total of 1030 lumbar spine radiographs performed in the ED of an academic medical center over a consecutive 3-month period were reviewed retrospectively. Referral indications were reviewed for adherence to 2021 American College of Radiology appropriateness guidelines for lower back pain, and referral patterns were evaluated among physician groups based on specialists' training and years in practice. 63.8% of lumbar spine radiographs were appropriate, with trauma being the most common indication. 36.2% of orders were inappropriate, with lower back pain of <6 weeks duration being the most common indication. Significant differences in inappropriate orders were found (P < .001) across physician groups: qualified Emergency Medicine specialists (20.9% inappropriate orders), specialists in training (27.8%), and non-specialists with ≥3 (60.0%) and <3 (36.9%) years in practice, respectively. Approximately one-third of lumbar spine radiographs performed in the ED were inappropriately ordered by American College of Radiology guidelines; specialists training and years in practice affected referral patterns. Integrating evidence-based appropriateness guidelines into the physician order workflow and targeting older non-specialists may promote more judicious imaging and reduce health care costs.

Prognostic Value of Tumor Budding in Urothelial Carcinoma: A Meta-Analysis and Systematic Review.

Recently, tumor budding (TB) has been suggested as a strong prognostic marker in urinary tract urothelial carcinoma (UC). The aim of this systematic review is to test the prognostic value of TB in UC by a meta-analysis of previously published studies. We systematically reviewed the literature related to TB by using the databases of Scopus, PubMed, and Web of Science. The search was limited to publications in the English language up to July 2022. There were 790 patients from 7 retrospective studies in which TB has been evaluated in UC. Two authors independently extracted the results from eligible studies. The meta-analysis of eligible studies revealed that TB is a significant prognosticator for progression-free survival in UC, with a hazard ratio (HR) of 3.51 (95% CI, 1.86-6.62; P < .001) in univariate analysis and a HR of 2.78 (95% CI, 1.57-4.93; P < .001) in multivariate analysis; a significant prognosticator for overall survival and cancer-specific survival in UC, with a HR of 3.07 (95% CI, 2.04-4.64; P < .001) and a HR of 2.18 (95% CI, 1.11-4.29; P = .02) respectively in univariate analysis. Our findings confirm that UC with a high TB count is at a high risk of progress. TB could be considered as an element in pathology reports and future oncologic staging systems.

The ongoing Streptococcus pyogenes (Group A Streptococcus) outbreak in London, United Kingdom, in December 2022: a molecular epidemiology study.

OBJECTIVES: Epidemiological and whole-genome sequencing analysis of an ongoing outbreak of Streptococcus pyogenes (Group A Streptococcus) in London (United Kingdom). METHODS: Prospective identification of Group A Streptococcus cases from a diagnostic laboratory serving central and south London between 27 November and 10 December 2022. Case notes were reviewed and isolates were retrieved. Case numbers were compared with the previous 5 years. Whole-genome sequencing was performed with long-read, nanopore technology for emm typing and identification of superantigen genes. Associations of pathogen-related factors with an invasive disease were assessed by single-variable and multi-variable logistic regression. RESULTS: Case numbers began increasing in October 2022 from a baseline of 2.0 cases per day, and in December 2022, the average daily case numbers reached 10.8 cases per day, four-fold the number usually seen in winter. A total of 113 cases were identified during the prospective study period. Three quarters (86/113, 76%) were paediatric cases, including 2 deaths. Of 113 cases, 11 (10%) were invasive. In total, 56 isolates were successfully sequenced, including 10 of 11 (91%) invasive isolates. The emm12 (33/56, 59%) and emm1 (9/56, 16%) types were predominant, with 7 of 9 (78%) emm1 isolates being from the M1uk clone. The majority of invasive isolates had superantigen genes spea (7/10, 70%) and spej (8/10, 80%), whereas, in non-invasive isolates, these superantigen genes were found less frequently (spea: 5/46, 11% and spej: 7/46, 15%). By multivariable analysis of pathogen-related factors, spea (OR 8.9, CI 1.4-57, p 0.020) and spej (OR 12, CI 1.8-78, p 0.011) were associated with invasive disease. CONCLUSIONS: emm12 and emm1 types predominate in the ongoing outbreak, which mainly affects children. In this outbreak, the spea and spej superantigen genes are associated with the severity of presentation.

Factors Predicting Return to Work After Inpatient Stroke Rehabilitation: A Retrospective Follow-up Study.

Objective: To determine the proportion of patients who return to work after inpatient stroke rehabilitation and to identify demographic, clinical, and functional predictive factors for its success. Design: A retrospective follow-up study of patients with stroke who were premorbidly working and had completed inpatient rehabilitation in a large metropolitan hospital between January 2016 and December 2017. They underwent a telephone interview at 2 years post discharge. Setting: Inpatient rehabilitation and follow-up post discharge. Participants: A total of 314 patients with stroke (73.9% male) with mean age of 58.9 at time of stroke (N=314). Results: A total of 46% of 314 participants returned to work. In multivariable logistic regression analysis, viewing return to work as important (odds ratio [OR], 11.90; 95% confidence interval [CI], 5.15-27.52), absence of language impairment (OR, 9.39; 95% CI, 3.01-29.34), ambulation FIM≥5 (supervision to independence level) on discharge (OR, 4.93; 95% CI, 2.44-9.98), cognitive FIM on discharge ≥25 (OR, 2.77; 95% CI, 1.19-6.47), employment in premorbid office work (OR, 2.67; 95% CI, 1.26-5.64), and a lower Charlson Comorbidity Index (CCI) score at discharge (OR, 0.83; 95% CI, 0.68-1.00) were associated with successful return to work. Conclusions: Viewing return to work as important, absence of language impairments on discharge, discharge ambulation FIM≥5, discharge cognitive FIM≥25, employment in premorbid office work, and a lower discharge CCI score were positive predictors of successful return to work.

Post-surgical thoracic spinal cord herniation following an unrepaired dural defect: a rare complication.

Surgery for ossification of the ligamentum flavum (OLF) comes with a relatively high risk of dural tear. We report a 50-year-old woman, who presented with symptomatic spinal stenosis from OLF at T11-T12 and lower lumbar spondylosis for which a single stage posterior decompression and instrumented fusion of both sites was done. Removal of the OLF resulted in a small dural tear with intact arachanoid which was covered using a fibrin sealant. In the first post-operative day, the patient's neurology started deteriorating. An MR scan was done to look for hematoma. It showed the spinal cord herniating out of the thecal sac at the operated level. Emergency re-operation was done to reduce the herniation and the dural defect was repaired. The patient gradually recovered to her best functional status. Based on this experience, we advise primary repair of inadvertent durotomies.

Resilience is a dirty word: misunderstood, and how we can truly build it.

Resilience is ubiquitous in everyday speech, academic literature and governmental policies. Yet it seems to have taken a narrow scope in healthcare, confined to individual and psychological resilience. This short essay aims to broaden the understanding of resilience to organisational levels and calls intensivists to take active roles in fostering resilience for their staff. The article explores firstly the background and etymology of resilience. It then challenges current approaches and briefly signposts some current work in the area. Some examples of structural factors which build individual resilience are listed, followed by a call for intensivists to take active roles to build future resilience. The need for interdisciplinary, cross-sectoral and multi-level approaches is vital to build future healthcare resilience, and we intensivists must continue to be advocates for systemic change.

Normative reference values and regression equations to predict the 6-minute walk distance in the Asian adult population aged 21-80 years.

Summary at a glance: The 6-min walk test (6MWT) is a widely used field walking test. This study reports the normative reference values (NRV) of distance walked during 6MWT (6MWD) in healthy Singaporeans (aged 21-80) and updates the 6MWD reference equations. This information may facilitate the interpretation of the 6MWD in clinical populations. Ethics approval: The Singapore Institute of Technology-Institutional Review Board (SIT-IRB Project Number: 2019099) approved this study to be carried out from June 2019 to January 2021. All participants gave written informed consent before data collection began. Background: The six-minute walk test (6MWT) is a widely adopted submaximal field-walking test to evaluate functional exercise capacity. This validated test is a reliable, safe, inexpensive, and straightforward assessment tool commonly used as an outcome measure, using the distance walked (6MWD) as the primary outcome. An earlier study has established the normative reference values (NRV) and equation in healthy Singaporeans - however, the small sample size and narrow age range curb adequate representation of the adult population profile. Objectives: This study aims to update the NRV and reference equations to predict the distance walked during 6MWT (6MWD) for healthy Singaporeans aged 21-80. Methods: This cross-sectional study recruited community-dwelling healthy subjects aged 21-80 via convenience sampling. Each subject completed two trials of 6MWT according to the standard protocol. Primary outcome measures included 6MWD, pre-and post-test heart rate (HR), oxygen saturation, and blood pressure (BP). Results: 172 healthy Singaporeans (females=90, males=82) participated. The overall mean 6MWD was 578.00±75.38 metres. The age-stratified mean 6MWD ranged from 601.3±71.79 metres (aged 21-39) to 519.02±55.42 metres (aged 60-80). Age, gender, and percentage maximum HR predicted (%PredHRmax) were the most significant variables (p<0.001). 6MWD reference equation=288.282(height,m)+27.463×Gender (male=1;female=0)+4.349(%predHRmax)+1.191 (HR reserve, bpm) -185.431-1.343(age,years)-1.614 (weight, kg), R2=58%. Applying equations from other studies to the Singaporean population resulted in an overestimation of the 6MWD. Conclusion: This study updated the NRV and reference equations of 6MWD for healthy Singaporeans aged between 21-80 years. This update revises the local benchmarks of 6MWD in Singapore, a widely adopted outcome measure.

Early Postoperative Loss of Disc Height Following Transforaminal and Lateral Lumbar Interbody Fusion: A Radiographic Analysis.

STUDY DESIGN: Retrospective comparative radiological study. PURPOSE: To analyze the difference in early disc height loss following transforaminal and lateral lumbar interbody fusion (TLIF and LLIF). OVERVIEW OF LITERATURE: Minimal disc height loss facilitated by the polyaxial screw heads can occur naturally due to mechanical loading following lumbar fusion procedures. This loss does not usually cause any significant foraminal narrowing. However, when there is concomitant cage subsidence, symptomatic foraminal compromise could occur, especially when posterior decompression is not performed. It is not known whether the type of procedure, TLIF or LLIF, could influence this phenomenon. METHODS: Retrospectively, patients who underwent TLIF and LLIF for various degenerative conditions were shortlisted. Each of their fused levels with the cage in situ was analyzed independently, and the preoperative, postoperative, and follow-up disc height measurements were compared between the groups. In addition, the total disc height loss since surgery was calculated at final follow-up and was compared between the groups. RESULTS: Forty-six patients (age, 64.1±8.9 years) with 70 cage levels, 35 in each group, were selected. Age, sex, construct length, preoperative disc height, cage height, and immediate postoperative disc height were similar between the groups. By 3 months, disc height of the TLIF group was significantly less and continued to decrease over time, unlike in the LLIF group. By 1 year, the TLIF group demonstrated greater disc height loss (2.30±1.3 mm) than the LLIF group (0.89±1.1 mm). However, none of the patients in either group had any symptomatic complications throughout follow-up. CONCLUSIONS: Although our study highlights the biomechanical advantage of LLIF over TLIF in maintaining disc height, none of the patients in our cohort had symptomatic complications or implant-related failures. Hence, TLIF, as it incorporates posterior decompression, remains a safe and reliable technique despite the potential for greater disc height loss.