A Second Space Age Spanning Omics, Platforms, and Medicine Across Orbits.

The recent acceleration of commercial, private, and multi-national spaceflight has created an unprecedented level of activity in low Earth orbit (LEO), concomitant with the highest-ever number of crewed missions entering space and preparations for exploration-class (>1 year) missions. Such rapid advancement into space from many new companies, countries, and space-related entities has enabled a"Second Space Age." This new era is also poised to leverage, for the first time, modern tools and methods of molecular biology and precision medicine, thus enabling precision aerospace medicine for the crews. The applications of these biomedical technologies and algorithms are diverse, encompassing multi-omic, single-cell, and spatial biology tools to investigate human and microbial responses to spaceflight. Additionally, they extend to the development of new imaging techniques, real-time cognitive assessments, physiological monitoring, and personalized risk profiles tailored for astronauts. Furthermore, these technologies enable advancements in pharmacogenomics (PGx), as well as the identification of novel spaceflight biomarkers and the development of corresponding countermeasures. In this review, we highlight some of the recent biomedical research from the National Aeronautics and Space Administration (NASA), Japan Aerospace Exploration Agency (JAXA), European Space Agency (ESA), and other space agencies, and also detail the commercial spaceflight sector's (e.g. SpaceX, Blue Origin, Axiom, Sierra Space) entrance into aerospace medicine and space biology, the first aerospace medicine biobank, and the myriad upcoming missions that will utilize these tools to ensure a permanent human presence beyond LEO, venturing out to other planets and moons.

Call for a framework for reporting evidence for life beyond Earth.

Our generation could realistically be the one to discover evidence of life beyond Earth. With this privileged potential comes responsibility. The magnitude of the question of whether we are alone in the Universe, and the public interest therein, opens the possibility that results may be taken to imply more than the observations support, or than the observers intend. As life-detection objectives become increasingly prominent in space sciences, it is essential to open a community dialogue about how to convey information in a subject matter that is diverse, complicated and has a high potential to be sensationalized. Establishing best practices for communicating about life detection can serve to set reasonable expectations on the early stages of a hugely challenging endeavour, attach value to incremental steps along the path, and build public trust by making clear that false starts and dead ends are an expected and potentially productive part of the scientific process. Here we endeavour to motivate and seed the discussion with basic considerations and offer an example of how such considerations might be incorporated and applied in a proof-of-concept-level framework. Everything mentioned herein, including the name of the confidence scale, is intended not as a prescription, but simply as the beginning of an important dialogue.

ExROPPP: Fast, accurate, and spin-pure calculation of the electronically excited states of organic hydrocarbon radicals.

Recent years have seen an explosion of interest in organic radicals due to their promise for highly efficient organic light-emitting diodes and molecular qubits. However, accurately and inexpensively computing their electronic structure has been challenging, especially for excited states, due to the spin-contamination problem. Furthermore, while alternacy or "pseudoparity" rules have guided the interpretation and prediction of the excited states of closed-shell hydrocarbons since the 1950s, similar general rules for hydrocarbon radicals have not to our knowledge been found yet. In this article, we present solutions to both of these challenges. First, we combine the extended configuration interaction singles method with Pariser-Parr-Pople (PPP) theory to obtain a method that we call ExROPPP (Extended Restricted Open-shell PPP) theory. We find that ExROPPP computes spin-pure excited states of hydrocarbon radicals with comparable accuracy to experiment as high-level general multi-configurational quasi-degenerate perturbation theory calculations but at a computational cost that is at least two orders of magnitude lower. We then use ExROPPP to derive widely applicable rules for the spectra of alternant hydrocarbon radicals, which are completely consistent with our computed results. These findings pave the way for highly accurate and efficient computation and prediction of the excited states of organic radicals.

Short Timeframe Prediction of Kidney Failure among Patients with Advanced Chronic Kidney Disease.

BACKGROUND: Development of a short timeframe (6-12 months) kidney failure risk prediction model may serve to improve transitions from advanced chronic kidney disease (CKD) to kidney failure and reduce rates of unplanned dialysis. The optimal model for short timeframe kidney failure risk prediction remains unknown. METHODS: This retrospective study included 1757 consecutive patients with advanced CKD (mean age 66 years, estimated glomerular filtration rate 18 mL/min/1.73 m2). We compared the performance of Cox regression models using (a) baseline variables alone, (b) time-varying variables and machine learning models, (c) random survival forest, (d) random forest classifier in the prediction of kidney failure over 6/12/24 months. Performance metrics included area under the receiver operating characteristic curve (AUC-ROC) and maximum precision at 70% recall (PrRe70). Top-performing models were applied to 2 independent external cohorts. RESULTS: Compared to the baseline Cox model, the machine learning and time-varying Cox models demonstrated higher 6-month performance [Cox baseline: AUC-ROC 0.85 (95% CI 0.84-0.86), PrRe70 0.53 (95% CI 0.51-0.55); Cox time-varying: AUC-ROC 0.88 (95% CI 0.87-0.89), PrRe70 0.62 (95% CI 0.60-0.64); random survival forest: AUC-ROC 0.87 (95% CI 0.86-0.88), PrRe70 0.61 (95% CI 0.57-0.64); random forest classifier AUC-ROC 0.88 (95% CI 0.87-0.89), PrRe70 0.62 (95% CI 0.59-0.65)]. These trends persisted, but were less pronounced, at 12 months. The random forest classifier was the highest performing model at 6 and 12 months. At 24 months, all models performed similarly. Model performance did not significantly degrade upon external validation. CONCLUSIONS: When predicting kidney failure over short timeframes among patients with advanced CKD, machine learning incorporating time-updated data provides enhanced performance compared with traditional Cox models.

RNA polymerase III limits longevity downstream of TORC1.

Three distinct RNA polymerases transcribe different classes of genes in the eukaryotic nucleus. RNA polymerase (Pol) III is the essential, evolutionarily conserved enzyme that generates short, non-coding RNAs, including tRNAs and 5S rRNA. The historical focus on transcription of protein-coding genes has left the roles of Pol III in organismal physiology relatively unexplored. Target of rapamycin kinase complex 1 (TORC1) regulates Pol III activity, and is also an important determinant of longevity. This raises the possibility that Pol III is involved in ageing. Here we show that Pol III limits lifespan downstream of TORC1. We find that a reduction in Pol III extends chronological lifespan in yeast and organismal lifespan in worms and flies. Inhibiting the activity of Pol III in the gut of adult worms or flies is sufficient to extend lifespan; in flies, longevity can be achieved by Pol III inhibition specifically in intestinal stem cells. The longevity phenotype is associated with amelioration of age-related gut pathology and functional decline, dampened protein synthesis and increased tolerance of proteostatic stress. Pol III acts on lifespan downstream of TORC1, and limiting Pol III activity in the adult gut achieves the full longevity benefit of systemic TORC1 inhibition. Hence, Pol III is a pivotal mediator of this key nutrient-signalling network for longevity; the growth-promoting anabolic activity of Pol III mediates the acceleration of ageing by TORC1. The evolutionary conservation of Pol III affirms its potential as a therapeutic target.

Computing the electronic circular dichroism spectrum of DNA quadruple helices of different topology: A critical test for a generalized excitonic model based on a fragment diabatization.

In this study, we exploit a recently developed fragment diabatization-based excitonic model, FrDEx, to simulate the electronic circular dichroism (ECD) spectra of three guanine-rich DNA sequences arranged in guanine quadruple helices with different topologies: thrombin binding aptamer (antiparallel), c-Myc promoter (parallel), and human telomeric sequence (3+1 hybrid). Starting from time-dependent density functional theory (TD-DFT) calculations with the M052X functional, we apply our protocol to parameterize the FrDEX Hamiltonian, which accounts for electron density overlap and includes both the coupling with charge transfer transitions and the effect of the surrounding bases on the local excitation of each chromophore. The TD-DFT/M052X spectral shapes are in good agreement with the experimental ones, the main source of discrepancy being related to the intrinsic error on the computed transition energies of guanine monomer. FrDEx spectra are fairly close to the reference TD-DFT ones, allowing a significant advance with respect to a more standard excitonic Hamiltonian. We also show that the ECD spectra are sensitive to the inclusion of the inner K + cation in the calculation.

A prospective observational study of the efficacy of ketamine for rescue analgesia in the postanesthesia recovery unit.

BACKGROUND: Early severe postoperative pain is frequently resistant to management with opioid analgesia alone. Perioperative low-dose ketamine as an analgesia adjunct has been studied extensively. Its efficacy as a rescue analgesic in the postanesthesia care unit (PACU) has not been determined. The objective of this study was to evaluate the analgesic efficacy of low-dose bolus ketamine for opioid-resistant pain in the PACU by measuring its effect on numerical rating scale (NRS) pain scores and opioid requirement. METHODS: This was a prospective observational study of adult noncardiac surgery patients with significant postoperative pain in the PACU. Patients were administered bolus doses of intravenous ketamine in 10-mg increments, repeated two to three times to an approximate maximum dose of 0.25 mg·kg-1. Primary outcomes were resting pain score reduction and opioid use from time of bolus ketamine administration to 30 min after administration of final ketamine bolus. The secondary outcome was incidence of side effects from ketamine administration. RESULTS: A convenience sample of 100 patients was chosen. The mean (standard deviation) NRS resting pain score reduction 30 min after iv ketamine administration was 2.7 (1.8) (P < 0.001). Patients with a history of previous opioid use or chronic pain were not more responsive to the effects of low-dose bolus ketamine. There were no ketamine-related adverse effects in any of the study patients. CONCLUSION: Administration of low-dose bolus ketamine in the PACU for severe opioid-resistant pain was associated with a significant improvement in analgesia in this observational study.

RéSUMé: CONTEXTE: La douleur postopératoire sévère précoce est souvent résistante à une prise en charge par analgésie opioïde seule. La kétamine périopératoire à faible dose en tant qu'analgésie adjuvante a fait l'objet d'études approfondies. Son efficacité en tant qu'analgésie de secours en salle de réveil est encore mal déterminée. L'objectif de cette étude était d'évaluer l'efficacité analgésique d'un bolus de kétamine à faible dose pour soulager la douleur résistante aux opioïdes en salle de réveil en mesurant son effet sur les scores de douleur sur une échelle d'évaluation numérique (EEN) et sur les besoins en opioïdes. MéTHODE: Il s'agissait d'une étude observationnelle prospective auprès de patients adultes ayant bénéficié d'une chirurgie non cardiaque et présentant une douleur postopératoire importante en salle de réveil. Les patients ont reçu des bolus de kétamine intraveineuse par tranches de 10 mg, répétés deux à trois fois jusqu'à une dose maximale approximative de 0,25 mg·kg−1. Les critères d'évaluation principaux étaient la réduction du score de douleur au repos et la consommation d'opioïdes à partir du moment de l'administration de kétamine en bolus jusqu'à 30 minutes après l'administration du bolus final de kétamine. Le critère d'évaluation secondaire était l'incidence d'effets secondaires liés à l'administration de kétamine. RéSULTATS: Un échantillon de commodité de 100 patients a été choisi. La réduction moyenne (écart type) du score de douleur au repos sur l'EEN 30 min après l'administration de kétamine iv était de 2,7 (1,8) (P < 0,001). Les patients ayant des antécédents de consommation antérieure d'opioïdes ou de douleur chronique n'étaient pas plus sensibles aux effets de la kétamine en bolus à faible dose. Il n'y a eu aucun effet indésirable lié à la kétamine chez aucun des patients de l'étude. CONCLUSION: L'administration de kétamine en bolus à faible dose en salle de réveil pour soulager la douleur sévère résistante aux opioïdes a été associée à une amélioration significative de l'analgésie dans cette étude observationnelle.

Mutational and biophysical robustness in a prestabilized monobody.

The fibronectin type III (FN3) monobody domain is a promising non-antibody scaffold, which features a less complex architecture than an antibody while maintaining analogous binding loops. We previously developed FN3Con, a hyperstable monobody derivative with diagnostic and therapeutic potential. Prestabilization of the scaffold mitigates the stability-function trade-off commonly associated with evolving a protein domain toward biological activity. Here, we aimed to examine if the FN3Con monobody could take on antibody-like binding to therapeutic targets, while retaining its extreme stability. We targeted the first of the Adnectin derivative of monobodies to reach clinical trials, which was engineered by directed evolution for binding to the therapeutic target VEGFR2; however, this function was gained at the expense of large losses in thermostability and increased oligomerization. In order to mitigate these losses, we grafted the binding loops from Adnectin-anti-VEGFR2 (CT-322) onto the prestabilized FN3Con scaffold to produce a domain that successfully bound with high affinity to the therapeutic target VEGFR2. This FN3Con-anti-VEGFR2 construct also maintains high thermostability, including remarkable long-term stability, retaining binding activity after 2 years of storage at 36 °C. Further investigations into buffer excipients doubled the presence of monomeric monobody in accelerated stability trials. These data suggest that loop grafting onto a prestabilized scaffold is a viable strategy for the development of monobody domains with desirable biophysical characteristics and that FN3Con is therefore well-suited to applications such as the evolution of multiple paratopes or shelf-stable diagnostics and therapeutics.

Solvent Effects on Ultrafast Charge Transfer Population: Insights from the Quantum Dynamics of Guanine-Cytosine in Chloroform.

Invited for the cover of this issue is the group of G. A. Worth, F. Santoro and R. Improta at UCL, ICOOM-CNR and IBB-CNR. The image depicts charge transfer from guanine to cytosine in solvent after the absorption of light. Read the full text of the article at 10.1002/chem.202201731.

Solvent Effects on Ultrafast Charge Transfer Population: Insights from the Quantum Dynamics of Guanine-Cytosine in Chloroform.

We study the ultrafast photoactivated dynamics of the hydrogen bonded dimer Guanine-Cytosine in chloroform solution, focusing on the population of the Guanine→Cytosine charge transfer state (GC-CT), an important elementary process for the photophysics and photochemistry of nucleic acids. We integrate a quantum dynamics propagation scheme, based on a linear vibronic model parameterized through time dependent density functional theory calculations, with four different solvation models, either implicit or explicit. On average, after 50 fs, 30∼40 % of the bright excited state population has been transferred to GC-CT. This process is thus fast and effective, especially when transferring from the Guanine bright excited states, in line with the available experimental studies. Independent of the adopted solvation model, the population of GC-CT is however disfavoured in solution with respect to the gas phase. We show that dynamical solvation effects are responsible for this puzzling result and assess the different chemical-physical effects modulating the population of CT states on the ultrafast time-scale. We also propose some simple analyses to predict how solvent can affect the population transfer between bright and CT states, showing that the effect of the solute/solvent electrostatic interactions on the energy of the CT state can provide a rather reliable indication of its possible population.

Machine Learning Study of Metabolic Networks vs ChEMBL Data of Antibacterial Compounds.

Antibacterial drugs (AD) change the metabolic status of bacteria, contributing to bacterial death. However, antibiotic resistance and the emergence of multidrug-resistant bacteria increase interest in understanding metabolic network (MN) mutations and the interaction of AD vs MN. In this study, we employed the IFPTML = Information Fusion (IF) + Perturbation Theory (PT) + Machine Learning (ML) algorithm on a huge dataset from the ChEMBL database, which contains >155,000 AD assays vs >40 MNs of multiple bacteria species. We built a linear discriminant analysis (LDA) and 17 ML models centered on the linear index and based on atoms to predict antibacterial compounds. The IFPTML-LDA model presented the following results for the training subset: specificity (Sp) = 76% out of 70,000 cases, sensitivity (Sn) = 70%, and Accuracy (Acc) = 73%. The same model also presented the following results for the validation subsets: Sp = 76%, Sn = 70%, and Acc = 73.1%. Among the IFPTML nonlinear models, the k nearest neighbors (KNN) showed the best results with Sn = 99.2%, Sp = 95.5%, Acc = 97.4%, and Area Under Receiver Operating Characteristic (AUROC) = 0.998 in training sets. In the validation series, the Random Forest had the best results: Sn = 93.96% and Sp = 87.02% (AUROC = 0.945). The IFPTML linear and nonlinear models regarding the ADs vs MNs have good statistical parameters, and they could contribute toward finding new metabolic mutations in antibiotic resistance and reducing time/costs in antibacterial drug research.

Serious incidents in testicular torsion management in England, 2007-2019: optimizing individual and training factors are the key to improved outcomes.

OBJECTIVES: To establish the healthcare factors that contribute to testicular torsion adverse events (orchidectomies) and 'near misses'. The secondary objective was to identify areas suitable for impactful quality improvement initiatives to be undertaken by National Health Service (NHS) healthcare providers nationally. MATERIALS AND METHODS: This was a retrospective record review and analysis, carried out in four phases. We applied the well-validated London Protocol patient safety incident analysis framework to all eligible serious incidents related to testicular torsion submitted by English NHS Trusts over a 12-year period to the Strategic Executive Information System database. Clinical reviewers established the incident population (Phase 1), were trained and piloted the feasibility of using the London Protocol (Phase 2), applied the protocol and themed the identified contributing factors linked to adverse events (orchidectomies) and near-misses (Phase 3), and reviewed the evidence for improvement interventions (Phase 4). RESULTS: Our search returned 992 serious incidents, of which 732 were eligible for study inclusion and analysis. Of those, 137 resulted in orchidectomies, equivalent to one serious incident resulting in orchidectomy per month, and 595 were near misses. Factors contributing to all incidents were: individual staff/training (38%); team (18%); work environment (16%); task and technology (14%); and institutional context (13%). Subgroup analysis of incidents resulting in orchidectomies vs near misses demonstrated a different pattern of factors, with individual staff/training factors significantly more prominent: individual/training (88%); work environment (8%); and task and technology (1%). No evidenced improvement interventions were found in the literature. CONCLUSION: This is the first study to our knowledge to systematically analyse and classify factors that are associated with loss of a testicle and related near-miss incidents in patients presenting with testicular torsion. In England, a significant number of orchidectomies occur annually as a consequence of healthcare serious incidents. In order to improve outcomes, we propose clinical support to aid the diagnosis of torsion, improved national clinical guidelines, development of specific standard operating procedures and (in the longer term) more exposure of trainees and medical students to urology to improve the testicular salvage rate.

Interventions for obstructive uropathy in advanced prostate cancer: a population-based study.

OBJECTIVES: To develop and validate a coding framework to identify interventions for upper tract obstructive uropathy (UTOU) in men with locally advanced and metastatic prostate cancer (PCa) using administrative hospital data to assess clinical outcomes. There are no population-based studies on the incidence, treatment, and outcomes of this complication. PATIENTS AND METHODS: Patients newly diagnosed with PCa between April 2014 and March 2019 were identified in the English cancer registry. A coding framework based on procedure (Office of Population Censuses and Surveys Classification of Surgical Operations and Procedures fourth edition) and diagnostic (International Classification of Diseases, 10th edition) codes was developed and validated. Subsequent clinical outcomes were determined using Hospital Episodes Statistics to determine the utility of the intervention. RESULTS: A total of 77 010 patients newly diagnosed with locally advanced, and 30 083 patients with metastatic PCa were identified. Of these, 1951 (1.8%) patients underwent an intervention for UTOU according to our coding framework: 830 (42.5%) had locally advanced disease and 1121 (57.5%) had metastatic disease. In all, 844 (43.3%) had a percutaneous nephrostomy (PCN), 473 (24.2%) had a PCN with antegrade stent, and 634 (32.5%) had a retrograde stent. The mean follow-up was 43.2 months. The cumulative incidence of the use of these interventions at 1, 3, and 5 years was 2.5%, 3.6% and 4.2% in men with metastases compared to 0.5%, 0.9% and 1.4% in men with locally advanced disease. CONCLUSION: A new coding framework, developed to identify procedures for UTOU was applied in the largest study to date of UTOU in men with primary locally advanced and metastatic PCa. Results demonstrated that 2% of men with locally advanced PCa and 4% of men with metastatic PCa require an intervention to resolve UTOU within 5 years of their PCa diagnosis.

Healthcare Professional and Patient Perceptions of Changes in Colorectal Cancer Care Delivery During the COVID-19 Pandemic and Impact on Health Inequalities.

BACKGROUND: The COVID-19 pandemic changed the way in which people were diagnosed and treated for cancer. We explored healthcare professional and patient perceptions of the main changes to colorectal cancer delivery during the COVID-19 pandemic and how they impacted on socioeconomic inequalities in care. METHODS: In 2020, using a qualitative approach, we interviewed patients (n = 15) who accessed primary care with colorectal cancer symptoms and were referred for further investigations. In 2021, we interviewed a wide range of healthcare professionals (n = 30) across the cancer care pathway and gathered national and local documents/guidelines regarding changes in colorectal cancer care. RESULTS: Changes with the potential to exacerbate inequalities in care, included: the move to remote consultations; changes in symptomatic triage, new COVID testing procedures/ways to access healthcare, changes in visitor policies and treatment (e.g., shorter course radiotherapy). Changes that improved patient access/convenience or the diagnostic process have the potential to reduce inequalities in care. DISCUSSION: Changes in healthcare delivery during the COVID-19 pandemic have the ongoing potential to exacerbate existing health inequalities due to changes in how patients are triaged, changes to diagnostic and disease management processes, reduced social support available to patients and potential over-reliance on digital first approaches. We provide several recommendations to help mitigate these harms, whilst harnessing the gains.

Alkynedicobalt mediated vinylogous Nazarov reactions.

The SnCl4 mediated reactions of cross conjugated aryl enynone-Co2(CO)6 and dienynone-Co2(CO)6 complexes afford benzocycloheptynone complexes or cycloheptenynone complexes in a thermal vinylogous Nazarov process. The rate of ring closure is strongly dependent on the ketone α-substituent.

Inverse molecular design from first principles: Tailoring organic chromophore spectra for optoelectronic applications.

The discovery of molecules with tailored optoelectronic properties, such as specific frequency and intensity of absorption or emission, is a major challenge in creating next-generation organic light-emitting diodes (OLEDs) and photovoltaics. This raises the following question: How can we predict a potential chemical structure from these properties? Approaches that attempt to tackle this inverse design problem include virtual screening, active machine learning, and genetic algorithms. However, these approaches rely on a molecular database or many electronic structure calculations, and significant computational savings could be achieved if there was prior knowledge of (i) whether the optoelectronic properties of a parent molecule could easily be improved and (ii) what morphing operations on a parent molecule could improve these properties. In this Perspective, we address both of these challenges from first principles. We first adapt the Thomas-Reiche-Kuhn sum rule to organic chromophores and show how this indicates how easily the absorption and emission of a molecule can be improved. We then show how by combining electronic structure theory and intensity borrowing perturbation theory we can predict whether or not the proposed morphing operations will achieve the desired spectral alteration, and thereby derive widely applicable design rules. We go on to provide proof-of-concept illustrations of this approach to optimizing the visible absorption of acenes and the emission of radical OLEDs. We believe that this approach can be integrated into genetic algorithms by biasing morphing operations in favor of those that are likely to be successful, leading to faster molecular discovery and greener chemistry.

A prospective observational study of persistent opioid use after complex foot and ankle surgery.

PURPOSE: The incidence of persistent postsurgical opioid use (PPOU) after complex foot and ankle surgery is unknown. We aimed to determine the incidence and characteristics of PPOU in opioid-naïve, occasional, and regular opioid users at baseline and at six weeks, three months, and six months postoperatively. METHODS: We conducted a prospective observational study in patients undergoing complex foot and ankle surgery over an 18-month period. Daily opioid consumption was recorded at the indicated intervals. Logistic regression models were fit to predict the risk of opioid use at these intervals. The Brief Pain Inventory (BPI) was used to record pain intensity and interference. Correlations were tested between opioid use and BPI interference parameters. RESULTS: Eighty-two out of 139 consecutively approached patients were included in the final analysis. Six percent (98.3% confidence interval [CI], 2 to 20) of patients who were not using opioids preoperatively at baseline were using opioids daily at three and six months after surgery. Fifty percent (98.3% CI, 26 to 73) of patients who were regular opioid users preoperatively continued to use opioids daily six months after surgery. All associations between BPI interference parameters and opioid use were estimated to be positive. CONCLUSION: The probability of using opioid analgesia six months after complex foot and ankle surgery was significantly higher in patients who used opioids preoperatively. Regular preoperative opioid use was associated with a greater risk of PPOU compared with occasional or "as required" opioid use prior to surgery.

RéSUMé: OBJECTIF: L'incidence de consommation persistante d'opioïdes après une chirurgie (CPOC) après une chirurgie complexe du pied et de la cheville est inconnue. Notre objectif était de déterminer l'incidence et les caractéristiques de la CPOC chez les utilisateurs d'opioïdes naïfs, occasionnels et réguliers avant leur opération, puis à six semaines, trois mois et six mois après l'opération. MéTHODE: Nous avons réalisé une étude observationnelle prospective sur une période de 18 mois auprès de patients bénéficiant d'une chirurgie complexe du pied et de la cheville. La consommation quotidienne d'opioïdes a été enregistrée aux intervalles indiqués. Des modèles de régression logistique ont été utilisés pour prédire le risque de consommation d'opioïdes à ces intervalles. Le Questionnaire concis de la douleur (QCD - version française du Brief Pain Inventory, BPI) a été utilisé pour enregistrer l'intensité de la douleur et son interférence. Des corrélations ont été testées entre la consommation d'opioïdes et les paramètres d'interférence du QCD. RéSULTATS: Quatre-vingt-deux des 139 patients approchés consécutivement ont été inclus dans notre analyse finale. Six pour cent (intervalle de confiance [IC] à 98,3 %, 2 à 20) des patients qui ne consommaient pas d'opioïdes avant l'opération utilisaient des opioïdes quotidiennement trois et six mois après la chirurgie. Cinquante pour cent (IC 98,3 %, 26 à 73) des patients qui étaient des consommateurs réguliers d'opioïdes avant l'opération ont continué à utiliser des opioïdes quotidiennement six mois après la chirurgie. Toutes les associations entre les paramètres d'interférence du QCD et la consommation d'opioïdes ont été estimées positives. CONCLUSION: La probabilité d'avoir recours à une analgésie opioïde six mois après une chirurgie complexe du pied et de la cheville était significativement plus élevée chez les patients qui consommaient déjà des opioïdes avant leur opération. La consommation régulière d'opioïdes avant l'opération a été associée à un risque plus élevé de CPOC par rapport à l'utilisation occasionnelle ou « au besoin ¼ d'opioïdes avant la chirurgie.

Elective surgery in ankle and foot disorders-best practices for management of pain: a guideline for clinicians.

PURPOSE: Complex elective foot and ankle surgeries are often associated with severe pain pre- and postoperatively. When inadequately managed, chronic postsurgical pain and long-term opioid use can result. As no standards currently exist, we aimed to develop best practice pain management guidelines. METHODS: A local steering committee (n = 16) surveyed 116 North American foot and ankle surgeons to understand the "current state" of practice. A multidisciplinary expert panel (n = 35) was then formed consisting of orthopedic surgeons, anesthesiologists, chronic pain physicians, primary care physicians, pharmacists, registered nurses, physiotherapists, and clinical psychologists. Each expert provided up to three pain management recommendations for each of the presurgery, intraoperative, inpatient postoperative, and postdischarge periods. These preliminary recommendations were reduced, refined, and sent to the expert panel and "current state" survey respondents to create a consensus document using a Delphi process conducted from September to December 2020. RESULTS: One thousand four hundred and five preliminary statements were summarized into 51 statements. Strong consensus (≥ 80% respondent agreement) was achieved in 53% of statements including the following: postsurgical opioid use risk should be assessed preoperatively; opioid-naïve patients should not start opioids preoperatively unless non-opioid multimodal analgesia fails; and if opioids are prescribed at discharge, patients should receive education regarding importance of tapering opioid use. There was no consensus regarding opioid weaning preoperatively. CONCLUSIONS: Using multidisciplinary experts and a Delphi process, strong consensus was achieved in many areas, showing considerable agreement despite limited evidence for standardized pain management in patients undergoing complex elective foot and ankle surgery. No consensus on important issues related to opioid prescribing and cessation highlights the need for research to determine best practice.

RéSUMé: OBJECTIF: Les chirurgies électives complexes du pied et de la cheville sont souvent associées à une douleur intense avant et après l'opération. Lorsque cette douleur est mal prise en charge, elle peut entraîner une douleur postopératoire chronique et une consommation d'opioïdes à long terme. Comme il n'existe actuellement aucune norme, nous avons cherché à élaborer des lignes directrices sur les meilleures pratiques en matière de prise en charge de la douleur. MéTHODE: Un comité directeur local (n = 16) a interrogé 116 chirurgiens nord-américains spécialistes du pied et de la cheville pour comprendre « l'état actuel ¼ de la pratique. Un groupe d'experts multidisciplinaire (n = 35) a ensuite été formé, composé de chirurgiens orthopédistes, d'anesthésiologistes, de médecins spécialistes de la douleur chronique, de médecins de soins primaires, de pharmaciens, d'infirmières autorisées, de physiothérapeutes et de psychologues cliniciens. Chaque expert a fourni jusqu'à trois recommandations de prise en charge de la douleur pour chacune des périodes suivantes : en préchirurgie, en peropératoire, pendant l'hospitalisation postopératoire et après le congé. Ces recommandations préliminaires ont été réduites, affinées et envoyées au groupe d'experts et aux répondants du sondage sur « l'état actuel ¼ afin de créer un document de consensus à l'aide d'une méthode de Delphi réalisée entre septembre et décembre 2020. RéSULTATS: Mille quatre cent cinq déclarations préliminaires ont été résumées en 51 énoncés. Un consensus fort (≥ 80 % des répondants étaient d'accord) a été atteint concernant 53 % des énoncés, notamment les suivants : le risque de consommation postopératoire d'opioïdes devrait être évalué avant l'opération; les patients naïfs aux opioïdes ne devraient pas commencer à prendre des opioïdes avant l'opération, à moins que l'analgésie multimodale non opioïde n'échoue; et si des opioïdes sont prescrits au congé, les patients devraient être informés de l'importance de réduire leur consommation d'opioïdes. Il n'y avait pas de consensus concernant le sevrage des opioïdes en période préopératoire. CONCLUSION: À l'aide d'experts multidisciplinaires et d'une méthode de Delphi, un fort consensus a été atteint dans de nombreux aspects, montrant un accord considérable malgré des données probantes limitées pour une prise en charge standardisée de la douleur chez les patients subissant une chirurgie élective complexe du pied et de la cheville. L'absence de consensus sur des questions importantes liées à la prescription et à l'interruption des opioïdes souligne la nécessité de recherches pour déterminer les pratiques exemplaires.

Symbiotic relationships through longitudinal integrated clerkships in general practice.

BACKGROUND: Longitudinal integrated clerkships (LICs) are an innovation in medical education that are often successfully implemented in general practice contexts. The aim of this study was to explore the experiences and perspectives of general practitioner (GP)-tutors on the impact of LICs on their practices, patients and the wider community. METHODS: GPs affiliated with the University of Limerick School of Medicine- LIC were invited to participate in in-depth interviews. Semi-structured interviews were conducted in person and over the phone and were based on a topic guide. The guide and approach to analysis were informed by symbiosis in medical education as a conceptual lens. Data were recorded, transcribed and analysed using an inductive thematic approach. RESULTS: Twenty-two GPs participated. Two main themes were identified from interviews: 'roles and relationships' and 'patient-centred physicians'. Five subthemes were identified which were: 'GP-role model', 'community of learning', and 'mentorship', 'student doctors' and 'serving the community'. CONCLUSION: LICs have the potential to develop more patient-centred future doctors, who have a greater understanding of how medicine is practised in the community. The LIC model appears to have a positive impact on all stakeholders but their success hinges on having adequate support for GPs and resourcing for the practices.

Supporting a Learning System in Pediatric Emergency Pathways: Using Organizational Comparisons, Serious Incidents, and Near-Miss Events to Improve the Diagnosis and Treatment of Testicular Torsion.

BACKGROUND: Scrotal pain is a common presentation to the emergency department requiring prompt investigation and management to identify testicular torsion and increase the opportunity for testicular salvage. Using national data obtained from the NHS Improvement, we aim to identify key suboptimal areas in the acute diagnosis and management of testicular torsion with a view to learning from these and improving outcomes. METHODS: A freedom of information request was made to all 134 hospital groups in England and Wales that manage testicular torsion. Serious incidents experienced by these hospitals were analyzed to see whether those with pediatric emergency departments fared better than those without. In addition, a qualitative thematic analysis of the NHS Improvement National Reporting and Learning System database over a 12-year period (2007-2019) was undertaken, to identify common themes associated with orchidectomies and "near-miss" events in the pediatric population. RESULTS: Three hundred four patient safety incidents were returned and divided into 62 orchidectomies and 242 near-miss events. The most common factor in the orchidectomy group was individual factors (83.9%). Misdiagnosis of symptomatic testicle was not significant when comparing ED to specialist surgeons (odds ratio = 1.46, P = 0.3842). Atypical presentation resulting in orchidectomy was significant when comparing ED with specialists (odds ratio = 6, P = 0.0355). Near-miss events, not leading to orchidectomy, are often due to a wider variety of factors. A Mann-Whitney U test showed that there was no statistical significance in incidents when comparing general ED units caring for all ages with pediatric EDs in terms of incidents ( U = 807.5, z = -1.124, P = 0.261). CONCLUSIONS: There is a need for education in ED about atypical presentation of testicular torsion and examination of scrotum in cases of lower abdominal pain. It is also vital that specialist teams are cognizant of the standard operating procedures relevant to scrotal pain and testicular within the organization and the wider clinical network. Finally, there should be a drive for annual collation of data in urology and ED units with regards to testicular torsion as patient safety incidents may be underreported.