External validation of a prognostic model to improve prediction of psychosis in primary care.

Background Early detection could reduce the duration of untreated psychosis. GPs are a vital part of the psychosis care pathway but find it difficult to detect the early features. An accurate risk prediction tool (P Risk) was developed to detect these. Aim The external validation of P Risk. Methods A retrospective cohort study using a validation dataset of 1,647,934 UK Clinical Practice Research Datalink primary care records linked to secondary care records. The same predictors (age, sex, ethnicity, social deprivation, consultations for suicidal behaviour, depression/anxiety and substance abuse, history of consultations for suicidal behaviour, smoking history and substance abuse and prescribed medications for depression/anxiety/PTSD/OCD and total number of consultations) were used as for P Risk development. Predictive risk, sensitivity, specificity, and likelihood ratios were calculated for various risk thresholds. Discrimination (Harrell's C) and calibration were calculated. Results were compared between the development (GOLD) and validation (AURUM) datasets. Findings Psychosis risk increased with values of the P Risk prognostic index. Incidence was highest in younger age groups and mainly higher in males. Harrell's C was 0.79 (95% CI 0.78, 0.79) in the validation dataset and 0.77 in the development dataset. A risk threshold of 1% gave sensitivity of 65.9% and specificity of 86.6%. Interpretation Further testing is required but P Risk has the potential to be used in primary care to detect future risk of psychosis.

Protecting Caribbean patients diagnosed with cancer from compounding disasters.

Caribbean small island developing states are becoming increasingly vulnerable to compounding disasters, prominently featuring climate-related hazards and pandemic diseases, which exacerbate existing barriers to cancer control in the region. We describe the complexities of cancer prevention and control efforts throughout the Caribbean small island developing states, including the unique challenges of people diagnosed with cancer in the region. We highlight potential solutions and strategies that concurrently address disaster adaptation and cancer control. Because Caribbean small island developing states are affected first and worst by the hazards of compounding disasters, the innovative solutions developed in the region are relevant for climate mitigation, disaster adaptation, and cancer control efforts globally. In the age of complex and cascading disaster scenarios, developing strategies to mitigate their effect on the cancer control continuum, and protecting the health and safety of people diagnosed with cancer from extreme events become increasingly urgent. The equitable development of such strategies relies on collaborative efforts among professionals whose diverse expertise from complementary fields infuses the local community perspective while focusing on implementing solutions.

The Effect of the COVID Pandemic on the Rate of Same-Day Discharge in Primary Hip and Knee Arthroplasty.

BACKGROUND: Same-day discharge (SDD) following primary total hip arthroplasty (THA) and total knee arthroplasty (TKA) started increasing prior to 2020. The purpose of this study was to evaluate the change in the rate of SDD after the pandemic and determine whether those changes became permanent. METHODS: The annual rate of SDD for 15,208 primary THA and TKA cases performed between January 1, 2015, and September 9, 2022, at a single institution was determined. We also examined changes in SDD patient demographics as well as differences in the 90-day complication rates of SDD and overnight patients. RESULTS: In 2015, the rate of SDD for primary arthroplasty was 24%, which grew annually to 29% in 2019. Postpandemic, the rate of SDD jumped above 50% and continued up to 64% by 2022. The biggest increase was in TKA, which went from under 10% SDD prepandemic to 50% by 2022. The average age and body mass index of SDD cases prepandemic increased significantly to 62 ± 9 years and 29.4 ± 5.3 (P < .01). Overnight patients had higher rates of 90-day postoperative complications (8.4 versus 4.2%, P < .00001). CONCLUSIONS: The pandemic caused major changes in the rate of SDD for primary THA and TKA, increasing in subsequent years. The SDD patients became older and heavier due to the expanded criteria for SDD cases. The 90-day postoperative complication rate was lower for SDD patients since higher risk patients were kept overnight. At the prepandemic rate, 29% of patients currently being sent home would have stayed overnight.

The CCJR® Charles A. Engh, Sr, MD. Excellence in Hip Research Award: The Evolution of Revision Hip Arthroplasty and Impact on the Trainee's Experience.

BACKGROUND: Advances in total hip arthroplasty (THA) have resulted in evolving revision indications and intraoperative techniques, which can influence the exposure of trainees to complex cases. We report 3 decades of revision experience from a tertiary referral center that trains fellows, comparing the reasons for revision and the complexity of revisions over time. METHODS: We retrospectively reviewed all revision THAs performed at our institution from 1990 to 2022. Revision diagnoses, components revised, types of revision implants used, and exposure techniques were collected. A "complex" revision was defined as a case that involved an extended trochanteric osteotomy, triflange and cup-cage construct, or acetabular augment. RESULTS: A total of 3,556 THA revisions were identified (108 revisions/year). Aseptic loosening was the most common indication in 1990 to 1999 (45 per year), but decreased to 28.3/year in 2010 to 2019. From 1990 to 1999 and 2010 to 2019, fracture increased from 3.1 to 7.3 per year, infection from 2.9/year to 16.9/year, and metallosis from 0.1 to 13.2 per year. Both component revision were common from 1990 to 1994 (42.6 per year), while polyethylene exchange was most common in 2010 to 2019 (43.3 per year). A decrease was observed in "complex" cases over time: 14.8 extended trochanteric osteotomies/year in 2000 to 2004 compared to 5.4 per year in 2018 to 2022, 4.5 triflange and cup-cage constructs/year in 2004 to 2007 compared to 0.8 per year in 2018 to 2022, and 4 acetabular augments per year in 2009 to 2012 compared to 1 per year in 2018 to 2022. CONCLUSIONS: Indications for revision have changed over the decades, while the number of "complex" revisions has gradually decreased, presumably due to advances in implants and materials. If this trend extends to other training institutions, the next generation of arthroplasty surgeons will have less exposure to complex revisions during their training.

Advanced Concepts in Outpatient Joint Arthroplasty.

As the adoption and utilization of outpatient total joint arthroplasty continues to grow, key developments have enabled surgeons to safely and effectively perform these surgeries while increasing patient satisfaction and operating room efficiency. Here, the authors will discuss the evidence-based principles that have guided this paradigm shift in joint arthroplasty surgery, as well as practical methods for selecting appropriate candidates and optimizing perioperative care. There will be 5 core efficiency principles reviewed that can be used to improve organizational management, streamline workflow, and overcome barriers in the ambulatory surgery center. Finally, future directions in outpatient surgery at the ASC, including the merits of implementing robot assistance and computer navigation, as well as expanding indications for revision surgeries, will be debated.

Outcomes Following Intraoperative Calcar Fractures During Cementless Total Hip Arthroplasty.

BACKGROUND: Intraoperative calcar fractures (IOCFs) are an established complication of cementless total hip arthroplasty (THA). Prompt recognition and management may prevent subsequent postoperative complications. This study aimed to evaluate the outcomes and revision rates of THAs with IOCFs identified and managed intraoperatively. METHODS: There were 11,438 primary cementless THAs performed at a single institution from 2009 to 2022. Prospectively collected data on cases with an IOCF was compared to cases without the complication. The fracture group had a lower body mass index (26.9 versus 28.9 kg/m2; P = .01). Patient age, sex, and mean follow-up (3.2 (0 to 12.8) versus 3.5 years (0 to 14); P = .45) were similar between groups. RESULTS: An IOCF occurred in 62 of 11,438 (0.54%) cases. The THAs done via a direct anterior approach experienced the lowest rate of fractures (31 of 7,505, 0.4%) compared to postero-lateral (27 of 3,759, 0.7%; P = .03) and lateral (4 of 165, 2.4%; P < .01) approaches. Of the IOCFs, 48 of 62 (77%) were managed with cerclage cabling, 4 of 62 (6.5%) with intraoperative stem design change and cabling, 4 of 62 (6.5%) with restricted weight-bearing, and 6 of 62 (9.7%) with no modification to the standard postoperative protocol. The IOCF group experienced one case of postoperative component subsidence. No subjects in the IOCF cohort required revision, and rates were similar between groups (0 of 62, 0% versus 215 of 11,376, 1.9%; P = .63). Postoperative Hip dysfunction and Osteoarthritis Outcome Score for Joint Replacement scores were comparable (85.7 versus 86.4; P = .80). CONCLUSIONS: Cementless THA complicated by IOCF had similar postoperative revision rates and patient-reported outcome measures at early follow-up when compared to patients not experiencing this complication. Surgeons may use these data to provide postoperative counseling on expectations and outcomes following these rare intraoperative events.

Nuclear export of circular RNA.

Circular RNAs (circRNAs), which are increasingly being implicated in a variety of functions in normal and cancerous cells1-5, are formed by back-splicing of precursor mRNAs in the nucleus6-10. circRNAs are predominantly localized in the cytoplasm, indicating that they must be exported from the nucleus. Here we identify a pathway that is specific for the nuclear export of circular RNA. This pathway requires Ran-GTP, exportin-2 and IGF2BP1. Enhancing the nuclear Ran-GTP gradient by depletion or chemical inhibition of the major protein exporter CRM1 selectively increases the nuclear export of circRNAs, while reducing the nuclear Ran-GTP gradient selectively blocks circRNA export. Depletion or knockout of exportin-2 specifically inhibits nuclear export of circRNA. Analysis of nuclear circRNA-binding proteins reveals that interaction between IGF2BP1 and circRNA is enhanced by Ran-GTP. The formation of circRNA export complexes in the nucleus is promoted by Ran-GTP through its interactions with exportin-2, circRNA and IGF2BP1. Our findings demonstrate that adaptors such as IGF2BP1 that bind directly to circular RNAs recruit Ran-GTP and exportin-2 to export circRNAs in a mechanism that is analogous to protein export, rather than mRNA export.

Drug resistance and vaccine target surveillance of Plasmodium falciparum using nanopore sequencing in Ghana.

Malaria results in over 600,000 deaths annually, with the highest burden of deaths in young children living in sub-Saharan Africa. Molecular surveillance can provide important information for malaria control policies, including detection of antimalarial drug resistance. However, genome sequencing capacity in malaria-endemic countries is limited. We designed and implemented an end-to-end workflow to detect Plasmodium falciparum antimalarial resistance markers and diversity in the vaccine target circumsporozoite protein (csp) using nanopore sequencing in Ghana. We analysed 196 clinical samples and showed that our method is rapid, robust, accurate and straightforward to implement. Importantly, our method could be applied to dried blood spot samples, which are readily collected in endemic settings. We report that P. falciparum parasites in Ghana are mostly susceptible to chloroquine, with persistent sulfadoxine-pyrimethamine resistance and no evidence of artemisinin resistance. Multiple single nucleotide polymorphisms were identified in csp, but their significance is uncertain. Our study demonstrates the feasibility of nanopore sequencing for malaria genomic surveillance in endemic countries.

The clinical, genomic, and microbiological profile of invasive multi-drug resistant Escherichia coli in a major teaching hospital in the United Kingdom.

Escherichia coli is a ubiquitous component of the human gut microbiome, but is also a common pathogen, causing around 40, 000 bloodstream infections (BSI) in the United Kingdom (UK) annually. The number of E. coli BSI has increased over the last decade in the UK, and emerging antimicrobial resistance (AMR) profiles threaten treatment options. Here, we combined clinical, epidemiological, and whole genome sequencing data with high content imaging to characterise over 300 E. coli isolates associated with BSI in a large teaching hospital in the East of England. Overall, only a limited number of sequence types (ST) were responsible for the majority of organisms causing invasive disease. The most abundant (20 % of all isolates) was ST131, of which around 90 % comprised the pandemic O25b:H4 group. ST131-O25b:H4 isolates were frequently multi-drug resistant (MDR), with a high prevalence of extended spectrum ß-lactamases (ESBL) and fluoroquinolone resistance. There was no association between AMR phenotypes and the source of E. coli bacteraemia or whether the infection was healthcare-associated. Several clusters of ST131 were genetically similar, potentially suggesting a shared transmission network. However, there was no clear epidemiological associations between these cases, and they included organisms from both healthcare-associated and non-healthcare-associated origins. The majority of ST131 isolates exhibited strong binding with an anti-O25b antibody, raising the possibility of developing rapid diagnostics targeting this pathogen. In summary, our data suggest that a restricted set of MDR E. coli populations can be maintained and spread across both community and healthcare settings in this location, contributing disproportionately to invasive disease and AMR.

The performance of FIT-based and other risk prediction models for colorectal neoplasia in symptomatic patients: a systematic review.

Background: Colorectal cancer (CRC) incidence and mortality are increasing internationally. Endoscopy services are under significant pressure with many overwhelmed. Faecal immunochemical testing (FIT) has been advocated to identify a high-risk population of symptomatic patients requiring definitive investigation by colonoscopy. Combining FIT with other factors in a risk prediction model could further improve performance in identifying those requiring investigation most urgently. We systematically reviewed performance of models predicting risk of CRC and/or advanced colorectal polyps (ACP) in symptomatic patients, with a particular focus on those models including FIT. Methods: The review protocol was published on PROSPERO (CRD42022314710). Searches were conducted from database inception to April 2023 in MEDLINE, EMBASE, Cochrane libraries, SCOPUS and CINAHL. Risk of bias of each study was assessed using The Prediction study Risk Of Bias Assessment Tool. A narrative synthesis based on the guidelines for Synthesis Without Meta-Analysis was performed due to study heterogeneity. Findings: We included 62 studies; 23 included FIT (n = 22) or guaiac Faecal Occult Blood Testing (n = 1) combined with one or more other variables. Twenty-one studies were conducted solely in primary care. Generally, prediction models including FIT consistently had good discriminatory ability for CRC/ACP (i.e. AUC >0.8) and performed better than models without FIT although some models without FIT also performed well. However, many studies did not present calibration and internal and external validation were limited. Two studies were rated as low risk of bias; neither model included FIT. Interpretation: Risk prediction models, including and not including FIT, show promise for identifying those most at risk of colorectal neoplasia. Substantial limitations in evidence remain, including heterogeneity, high risk of bias, and lack of external validation. Further evaluation in studies adhering to gold standard methodology, in appropriate populations, is required before widespread adoption in clinical practice. Funding: National Institute for Health and Care Research (NIHR) [Health Technology Assessment Programme (HTA) Programme (Project number 133852).

Nanopore sequencing for malaria molecular surveillance: opportunities and challenges.

Nanopore-based sequencing platforms offer the potential for affordable malaria molecular surveillance (MMS) in resource-limited settings to track and ultimately counteract emerging threats, such as drug resistance and diagnostic escape. Here, we discuss opportunities and challenges to implementing MMS using nanopore sequencing, highlighting priority areas for technical development and innovation.

Colorectal cancer in symptomatic patients: How to improve the diagnostic pathway.

Even in countries with national screening programmes for colorectal cancer, most cancers are identified after the patient has developed symptoms. The patients present these symptoms usually to primary care, or in some countries to specialist care. In either healthcare setting, the clinician has to consider cancer to be a possibility, then to perform triage investigations, followed by definitive investigation, usually by colonoscopy. This apparently simple pathway is not simple: most symptoms of colorectal cancer are more likely to represent benign disease than cancer, and each of these stages represents selection of patients into a higher-risk pool. This article summarises a symptom-based approach to selection and initial investigation of such patients in primary care. Some special groups need particular attention, including the younger patient, those with an inherited predisposition to cancer, and those with co-morbidities.

Does Powered Femoral Broaching Compromise Patient Safety in Total Hip Arthroplasty?

Background: During manual broaching (MB) in total hip arthroplasty (THA), off-axis forces delivered to the proximal femur and broach malalignment can lead to fractures and cortical perforations. Powered broaching (PB) is a novel alternative that delivers consistent impaction forces and reduces workload. This is the first large-scale study to compare intraoperative and 90-day rates of periprosthetic femur fractures (PFFs) and perforations in THA performed using MB vs PB. Methods: Our institutional database was reviewed for all patients undergoing primary cementless direct anterior THA from 2016 to 2021. Three surgeons performing 2048 THAs (MB = 800; PB = 1248) using the same stem design were included. PFFs and perforations within 90 days of the index procedure were compared. Differences in length of surgery and demographics were assessed. Results: Calcar fractures occurred in <1% of patients (PB [0.96%, 12/1248] vs MB [0.25%, 2/800]; P = .06). Rates of trochanteric fractures did not differ (PB = 0.32% [4/1248] vs MB = 0.38% [3/800]; P = .84). Cortical perforations occurred in 0.24% (3/1248) of the PB cohort and in 0.75% (6/800) of the MB cohort (P = .09). No revisions due to aseptic loosening or PFF occurred within 120 days of surgery. Conclusions: Our single-center experience with powered femoral broaching in THA demonstrates PB is a safe and efficient means of performing direct anterior THA. Low rates (<1%) of PFF, perforation, and revision can be achieved. Given our positive experience with PB, all surgeon authors utilize PB nearly exclusively for elective primary direct anterior THA.

A bipartite function of ESRRB can integrate signaling over time to balance self-renewal and differentiation.

Cooperative DNA binding of transcription factors (TFs) integrates the cellular context to support cell specification during development. Naive mouse embryonic stem cells are derived from early development and can sustain their pluripotent identity indefinitely. Here, we ask whether TFs associated with pluripotency evolved to directly support this state or if the state emerges from their combinatorial action. NANOG and ESRRB are key pluripotency factors that co-bind DNA. We find that when both factors are expressed, ESRRB supports pluripotency. However, when NANOG is absent, ESRRB supports a bistable culture of cells with an embryo-like primitive endoderm identity ancillary to pluripotency. The stoichiometry between NANOG and ESRRB allows quantitative titration of this differentiation, and in silico modeling of bipartite ESRRB activity suggests it safeguards plasticity in differentiation. Thus, the concerted activity of cooperative TFs can transform their effect to sustain intermediate cell identities and allow ex vivo expansion of immortal stem cells. A record of this paper's transparent peer review process is included in the supplemental information.

Readmission rate and healthcare utilization outcomes of computer-assisted fluoroscopy-based hip navigation versus manual total hip arthroplasty.

INTRODUCTION: The study evaluates the technology of fluoroscopy-based hip navigation that has shown to improve implant positioning in total hip arthroplasty (THA). METHODS: Premier Healthcare data for patients undergoing manual THA or fluoroscopy-based hip navigation THA between 1 January 2016-30 September 2021, were analyzed 90- and 365-day post-THA. The primary outcome was inpatient readmission. Secondary outcomes were operating room (OR) time, length of stay, discharge status, and hospital costs. Baseline covariate differences were balanced using fine stratification and analyzed using generalized linear models. RESULTS: Among 4,080 fluoroscopy-based hip navigation THA and 429,533 manual THA balanced patients, hip-related readmission rates were statistically significantly lower for the fluoroscopy-based hip navigation THA cohort vs. manual THA for both 90-day (odd ratio [95% CI]: 0.69 [0.52 to 0.91] and 365-day (0.63 [0.49 to 0.81] follow-up. OR time was higher with fluoroscopy-based hip navigation THA vs. manual THA (134.65 vs. 132.04 minutes); however, fluoroscopy-based hip navigation THA patients were more likely to be discharged to home (93.73% vs. 90.11%) vs. manual THA. Hospital costs were not different between cohorts at 90- and 365-day post-operative. CONCLUSIONS: Fluoroscopy-based hip navigation THA resulted in fewer readmissions, greater discharge to home, and similar hospital costs compared to manual THA.

Computer-assisted solutions are becoming more ubiquitous in surgical procedures. However, most of the current research is limited to small sample size and limited economic endpoints. The current study utilizes hospital billing data and fine stratification methodology to address the issue around sample size and covariate balancing. Hospital billing data provide a large sample across the US along with hospital costs that can be broken into different categories. Fine stratification methodology allows for covariate balancing while keeping all the samples. It is particularly advantageous when the treated or exposed group represents less than 5% of the entire cohort for a given study, as was observed in this study. Covariate balancing was done on patient, provider (hospital) and surgeon characteristics to minimize confounding. Furthermore, a generalized linear model was utilized to minimize any residual confounding. The study evaluated both short term (3-month) and long term (1-year) outcomes. Study suggested clinical benefits in using computer-assisted fluoroscopy-based hip navigation system in THA compared to manual THA as well as showed cost parity between computer-assisted fluoroscopy-based hip navigation system in THA and manual THA.