Potentiation of the axis involving pentose phosphate pathway/NADPH oxidase/reactive oxygen species drives higher IL-10 production in monocytes of Sub-Saharan Africans.

Cellular metabolism is a key determinant of immune cell function. Here we found that CD14+ monocytes from Sub-Saharan Africans produce higher levels of IL-10 following TLR-4 stimulation and are bioenergetically distinct from monocytes from Europeans. Through metabolomic profiling, we identified the higher IL-10 production to be driven by increased baseline production of NADPH oxidase-dependent reactive oxygen species, supported by enhanced pentose phosphate pathway activity. Together, these data indicate that NADPH oxidase-derived ROS is a metabolic checkpoint in monocytes that governs their inflammatory profile and uncovers a metabolic basis for immunological differences across geographically distinct populations.

KRAS promotes GLI2-dependent transcription during pancreatic carcinogenesis.

Aberrant activation of GLI transcription factors has been implicated in the pathogenesis of different tumor types including pancreatic ductal adenocarcinoma (PDAC). However, the mechanistic link with established drivers of this disease remains in part elusive. Here, using a new genetically-engineered mouse model overexpressing constitutively active mouse form of GLI2 and a combination of genome wide assays, we provide evidence of a novel mechanism underlying the interplay between KRAS, a major driver of PDAC development, and GLI2 to control oncogenic gene expression. These mice, also expressing KrasG12D, show significantly reduced median survival rate and accelerated tumorigenesis compared to the KrasG12D only expressing mice. Analysis of the mechanism using RNA-seq demonstrate higher levels of GLI2 targets, particularly tumor growth promoting genes including Ccnd1, N-Myc and Bcl2, in KrasG12D mutant cells. Further, ChIP-seq studies showed that in these cells KrasG12D increases the levels of H3K4me3 at the promoter of GLI2 targets without affecting significantly the levels of other major active chromatin marks. Importantly, Gli2 knockdown reduces H3K4me3 enrichment and gene expression induced by mutant Kras. In summary, we demonstrate that Gli2 plays a significant role in pancreatic carcinogenesis by acting as a downstream effector of KrasG12D to control gene expression.

Neurotoxicology: a clinical systems-based review.

Neurological disease caused by toxins is widespread but under-recognised. Despite increasing public interest and a growing number of novel potential neurotoxins, diagnosis of neurotoxic disease is often delayed or missed, resulting in poorer patient outcomes. This article discusses neurotoxic syndromes using a systems-based approach, focusing on environmental and occupational agents. We do not discuss recreational drugs, pharmaceutical agents or developmental neurotoxins in detail. We aim to provide neurologists with a working understanding of the scenarios in which a clinical presentation may be due to a neurotoxin and how to approach confirmation of the diagnosis.

Association Between the Dialysate Bicarbonate and the Pre-dialysis Serum Bicarbonate Concentration in Maintenance Hemodialysis: A Retrospective Cohort Study.

Background: It is unclear whether the use of higher dialysate bicarbonate concentrations is associated with clinically relevant changes in the pre-dialysis serum bicarbonate concentration. Objective: The objective is to examine the association between the dialysate bicarbonate prescription and the pre-dialysis serum bicarbonate concentration. Design: This is a retrospective cohort study. Setting: The study was performed using linked administrative health care databases in Ontario, Canada. Patients: Prevalent adults receiving maintenance in-center hemodialysis as of April 1, 2020 (n = 5414) were included. Measurements: Patients were grouped into the following dialysate bicarbonate categories at the dialysis center-level: individualized (adjustment based on pre-dialysis serum bicarbonate concentration) or standardized (>90% of patients received the same dialysate bicarbonate concentration). The standardized category was stratified by concentration: 35, 36 to 37, and ≥38 mmol/L. The primary outcome was the mean outpatient pre-dialysis serum bicarbonate concentration at the patient level. Methods: We examined the association between dialysate bicarbonate category and pre-dialysis serum bicarbonate using an adjusted linear mixed model. Results: All dialysate bicarbonate categories had a mean pre-dialysis serum bicarbonate concentration within the normal range. In the individualized category, 91% achieved a pre-dialysis serum bicarbonate ≥22 mmol/L, compared to 87% in the standardized category. Patients in the standardized category tended to have a serum bicarbonate that was 0.25 (95% confidence interval [CI] = -0.93, 0.43) mmol/L lower than patients in the individualized category. Relative to patients in the 35 mmol/L category, patients in the 36 to 37 and ≥38 mmol/L categories tended to have a serum bicarbonate that was 0.70 (95% CI = -0.30, 1.70) mmol/L and 0.87 (95% CI = 0.14, 1.60) mmol/L higher, respectively. There was no effect modification by age, sex, or history of chronic lung disease. Limitations: We could not directly confirm that all laboratory measurements were pre-dialysis. Data on prescribed dialysate bicarbonate concentrations for individual dialysis sessions were not available, which may have led to some misclassification, and adherence to a practice of individualization could not be measured. Residual confounding is possible. Conclusions: We found no significant difference in the pre-dialysis serum bicarbonate concentration irrespective of whether an individualized or standardized dialysate bicarbonate was used. Dialysate bicarbonate concentrations ≥38 mmol/L (vs 35 mmol/L) may increase the pre-dialysis serum bicarbonate concentration by 0.9 mmol/L.

Contexte: On ignore si des concentrations plus élevées de bicarbonate dans le dialysat sont associées à des changements cliniquement significatifs dans le taux de bicarbonate sérique prédialyse. Objectif: Examiner l'association entre la prescription de bicarbonate du dialysat et le taux de bicarbonate sérique prédialyse. Conception: Étude de cohorte rétrospective. Cadre: Étude réalisée en Ontario (Canada) à partir des données administratives de santé. Sujets: Ont été inclus les adultes prévalents qui recevaient une hémodialyse chronique en centre le 1er avril 2020 (n=5 414). Mesures: Les sujets ont été regroupés dans les catégories suivantes de concentration en bicarbonate dans le dialysat utilisée dans leur unité de dialyse: individualisée (ajustée selon le taux de bicarbonate sérique prédialyse) ou normalisée (même concentration pour >90% des sujets). La catégorie « standardisée ¼ a été stratifiée selon la concentration: 35 mmol/L, 36 à 37 mmol/L et ≥38 mmol/L. Le principal critère d'évaluation était le taux moyen de bicarbonate sérique prédialyse en ambulatoire au niveau du patient. Méthodologie: Nous avons examiné l'association entre la catégorie de concentration en bicarbonate du dialysat et le taux de bicarbonate sérique prédialyse à l'aide d'un modèle linéaire mixte corrigé. Résultats: Pour toutes les catégories de concentration en bicarbonate du dialysat, le taux moyen de bicarbonate sérique prédialyse était dans la plage normale. Dans la catégorie « individualisée ¼, 91% des sujets avaient un taux de bicarbonate sérique prédialyse de ≥22 mmol/L, comparativement à 87% dans la catégorie « standardisée ¼. Les patients de la catégorie « standardisée ¼ tendaient à avoir un taux de bicarbonate sérique de 0,25 mmol/L (IC 95%: -0,93 à 0,43) inférieur à celui des patients de la catégorie « individualisée ¼. Comparé aux patients de la catégorie 35 mmol/L, les patients des catégories 36 à 37 mmol/L et ≥38 mmol/L tendaient respectivement à avoir un taux de bicarbonate sérique de 0,70 mmol/L (IC 95%: -0,30 à 1,70) et de 0,87 mmol/L (IC 95%: 0,14 à 1,60) plus élevé. L'âge, le sexe ou les antécédents de maladie pulmonaire chronique n'ont pas semblé modifier l'effet. Limites: Il n'a pas été possible de confirmer directement que toutes les mesures de laboratoire avaient été effectuées avant la dialyse. Les données sur les concentrations de bicarbonate prescrites pour les séances de dialyse individuelles n'étaient pas disponibles, ce qui peut avoir conduit à une classification erronée. De plus, l'observance d'une pratique d'individualisation n'a pas pu être mesurée. Une confusion résiduelle est possible. Conclusion: Nous n'avons observé aucune différence significative dans les taux de bicarbonate sériques prédialyse, qu'on ait utilisé une concentration individualisée ou standardisée de bicarbonate dans le dialysat. L'utilisation d'un dialysat à ≥38 mmol/L (c. 35 mmol/L) de bicarbonate peut entraîner une hausse de 0,9 mmol/L du taux de bicarbonate sérique prédialyse.

Reducing alcohol harms whilst minimising impact on hospitality businesses: 'Sweetspot' policy options.

BACKGROUND: During COVID-19, hospitality businesses (e.g. bars, restaurants) were closed/restricted whilst off-sales of alcohol increased, with health consequences. Post-covid, governments face lobbying to support such businesses, but many health services remain under pressure. We appraised 'sweetspot' policy options: those with potential to benefit public services and health, whilst avoiding or minimising negative impact on the hospitality sector. METHODS: We conducted rapid non-systematic evidence reviews using index papers, citation searches and team knowledge to summarise the literature relating to four possible 'sweetspot' policy areas: pricing interventions (9 systematic reviews (SR); 14 papers/reports); regulation of online sales (1 SR; 1 paper); place-shaping (2 SRs; 18 papers/reports); and violence reduction initiatives (9 SRs; 24 papers/reports); and led two expert workshops (n = 11). RESULTS: Interventions that raise the price of cheaper shop-bought alcohol appear promising as 'sweetspot' policies; any impact on hospitality is likely small and potentially positive. Restrictions on online sales such as speed or timing of delivery may reduce harm and diversion of consumption from on-trade to home settings. Place-shaping is not well-supported by evidence and experts were sceptical. Reduced late-night trading hours likely reduce violence; evidence of impact on hospitality is scant. Other violence reduction initiatives may modestly reduce harms whilst supporting hospitality, but require resources to deliver multiple measures simultaneously in partnership. CONCLUSIONS: Available evidence and expert views point to regulation of pricing and online sales as having greatest potential as 'sweetspot' alcohol policies, reducing alcohol harm whilst minimising negative impact on hospitality businesses.

Evaluating Real-World Implementation of INFORM (Improving Nursing Home Care through Feedback on Performance Data): An Improvement Initiative in Canadian Nursing Homes.

BACKGROUND: INFORM (Improving Nursing Home Care through Feedback on Performance Data) was a research intervention that equipped nursing home managers with skills to conduct local improvement projects and supported them in improving performance through modifiable elements in their units. Prior reports have found positive and sustained outcomes from INFORM intervention. In this article, the authors report findings from a formative service evaluation of INFORM as modified for implementation in real-world settings. METHODS: INFORM was transformed for real-world implementation with an initial cohort of 26 nursing homes in British Columbia, Canada (INFORM BC). Three stakeholder groups were involved: nursing home teams, an academic team that modified INFORM for implementation, and a BC team that implemented INFORM and coached participating nursing home teams in applying it locally. Service evaluation was conducted drawing on participants from all three stakeholder groups, using convenience sampling, with numbers varying by data source. Using a mixed methods design, outcome data included qualitative and quantitative assessment of surveys, discussions, observations, and a review of documents and resources. RESULTS: The majority of nursing home teams reported positive outcomes relative to the usefulness and relevance of the initiative for local needs despite a number of operational challenges during implementation. A key factor in their success was combining targeted external support with the opportunity to set goals and measure success locally. Challenges included a lack of time at the nursing home level, COVID-19-related disruptions, and issues with role clarity and alignment of expectations among the academic and BC teams. CONCLUSION: INFORM BC advanced the processes of change planning and transferable learning among nursing home managers and their local teams. Success was facilitated externally but defined and achieved locally. Future iterations should probe outcome sustainability and how nursing home teams adapt the INFORM approach in practice.

Correction: Highly-sensitive wafer-scale transfer-free graphene MEMS condenser microphones.

[This corrects the article DOI: 10.1038/s41378-024-00656-x.].

Sertraline, citalopram and paroxetine in lactation: passage into breastmilk and infant exposure.

Objectives: This study aimed to investigate the plasma and breastmilk concentrations for sertraline, citalopram and paroxetine for assessment of the Milk/Plasma (M/P) ratio and Absolute Infant Dose (AID), and to determine actual infant drug exposure through breastfeeding. Subsequently, informed recommendations will be formulated regarding the advisability of breastfeeding in women undergoing treatment with the three most widely used antidepressants. Methods: A pharmacokinetic study in lactating women and their infants using sertraline, citalopram or paroxetine was performed. Paired breastmilk and plasma samples and single point infant plasma samples were collected to determine antidepressant concentrations. An Area Under the Curve (AUC) based approach with the trapezoidal rule was used to calculate M/P ratios and AID for all three antidepressants by combining all measured concentrations for the same dose. Results: Thirty-seven lactating women and their infants participated in this study. 111 paired breastmilk and plasma samples and 37 single point infant plasma samples were collected. Detectable concentrations of sertraline, citalopram and paroxetine were present in all breastmilk samples. For sertraline and citalopram M/P ratio is above one, indicating higher breastmilk than plasma concentrations, however, drug exposure by breastmilk did not lead to detectable plasma drug levels in any of the 15 infants for sertraline, for nine (out of 13) infants for citalopram and for eight (out of nine) infants for paroxetine. Conclusion: Given the well-known benefits of breastfeeding, our findings support breastfeeding of infants by mothers who are taking sertraline, citalopram or paroxetine is safe. Sertraline and paroxetine are the preferred antidepressants during breastfeeding, reaching mostly undetectable infant drug levels.

Exploring aperiodic activity in first episode schizophrenia spectrum psychosis: A resting-state EEG analysis.

Abnormalities in brain oscillatory patterns have long been observed in schizophrenia and psychotic disorders more broadly. However, far less is known about aperiodic neural activity in these disorders, which has been linked to excitation/inhibition balance and neuronal population spiking within the brain. Here, we analysed resting-state electroencephalographic (EEG) recordings from 43 first episode schizophrenia spectrum psychosis (FESSP) patients and 28 healthy controls to examine whether aperiodic activity is disrupted in FESSP. We further assessed potential associations between aperiodic activity in FESSP and clinical symptom severity using the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Negative Symptoms (SANS), and the Scale for the Assessment of Positive Symptoms (SAPS). We found no significant differences in either the 1/f-like aperiodic exponent or the broadband aperiodic offset between the FESSP and healthy control groups when analysing the global neural signal averaged across all EEG electrodes. Bayesian analyses further supported these non-significant findings. However, additional non-parametric cluster-based permutation analyses did identify reduced aperiodic offset in the FESSP group, relative to controls across broad central, temporal, parietal and select frontal regions. No associations were found between either exponent or offset and clinical symptom severity when examining all FESSP participants, irrespective of antipsychotic medication status. However, offset was shown to predict BPRS and SANS scores in medication naive patients. In sum, this research presents an initial analysis of aperiodic neural activity in FESSP, offering preliminary evidence of altered aperiodic offset in this disorder. This contributes to a broader understanding of disrupted neural dynamics in early psychosis.

Enhanced osteochondral repair by leukocyte-depleted platelet-rich plasma in combination with adipose-derived mesenchymal stromal cells encapsulated in a three-dimensional photocrosslinked injectable hydrogel in a rabbit model.

INTRODUCTION: Intra-articular injection of adipose-derived mesenchymal stromal cells (ASCs) and/or platelet-rich plasma (PRP) have been reported to independently and synergistically improve healing of osteochondral lesions in animal models. However, their independent and combined effects when localized to an osteochondral lesion by encapsulation within a photocrosslinkable methacrylated gelatin hydrogel (GelMA) have not been explored. Herein we investigated a unique combination of allogeneic ASCs and PRP embedded in GelMA as a single-stage treatment for osteochondral regeneration in a rabbit model. METHODS: Thirty mature rabbits were divided into six experimental groups: (1) Sham; (2) Defect; (3) GelMA; (4) GelMA + ASCs; (5) GelMA + PRP; and (6) GelMA + ASCs + PRP.At 12 weeks following surgical repair, osteochondral regeneration was assessed on the basis of gross appearance, biomechanical properties, histological and immunohistochemical characteristics, and subchondral bone volume. RESULTS: In terms of mechanical property reflecting the ability of neotissue to bear stress, PRP only group were significantly lower than the Sham group (p = 0.0098). On the other hand, ASCs only and ASCs combined with PRP groups did not exhibit significantly difference, which suggesting that incorporation of ASCs assists in restoring the ability of the neotissue to bear stresses similarly to native tissue (p = 0.346, p = 0.40, respectively). Safranin O in ASCs combined with PRP group was significantly higher than the Defect and GelMA only groups (p = 0.0009, p = 0.0017, respectively). Additionally, ASCs only and ASCs combined with PRP groups presented especially strong staining for collagen type II. Surprisingly, PRP only and PRP + ASCs groups tended to exhibit higher collagen type I and collagen type X staining compared to ASCs only group, suggesting a potential PRP-mediated hypertrophic effect. CONCLUSION: Regeneration of a focal osteochondral defect in a rabbit model was improved by a single-stage treatment of a photocrosslinked hydrogel containing allogenic ASCs and autologous PRP, with the combination of ASCs and PRP producing superior benefit than either alone. No experimental construct fully restored all properties of the native, healthy osteochondral unit, which may require longer follow-up or further modification of PRP and/or ASCs characteristics.

Estimation of minimum foot clearance using a single foot-mounted inertial sensor and personalized foot geometry scan.

The real-world measurement of minimum foot clearance (mFC) during the swing phase of gait is critical in efforts to understand and reduce the risk of trip-and-fall incidents in populations with gait impairments. Past research has focused on measuring clearance of a single point on a person's foot, typically the toe-however, this may overestimate mFC and may even be the wrong region of the foot in cases of gait impairments or interventions. In this work, we present a novel method to reconstruct the swing-phase trajectory of an arbitrary number of points on a person's shoe and estimate the instantaneous height and location of whole-foot mFC. This is achieved using a single foot-mounted inertial sensor and personalized shoe geometry scan, assuming a rigid-body IMU-shoe system. This combination allows collection and analysis using out-of-lab tests, potentially including clinical environments. Validation of single marker location using the proposed method vs. motion capture showed height errors with bias less than 0.05 mm, and 95% confidence interval of - 8.18 to + 8.09 mm. The method is demonstrated in an example data set comparing different interventions for foot drop, and it shows clear differences among no intervention, functional electrical stimulation, and ankle-foot orthosis conditions. This method offers researchers and clinicians a rich understanding of a person's gait by providing objective 3D foot kinematics and allowing a unique opportunity to view the regions of the foot where minimum clearance occurs. This information can contribute to a more informed recommendation of specific interventions or assistive technology than is currently possible in standard clinical practice.

Restoring L4-S1 Lordosis Shape in Severe Sagittal Deformity: Impact of Correction Techniques on Alignment and Complication Profile.

BACKGROUND CONTEXT: Severe sagittal plane deformity with loss of L4-S1 lordosis is disabling and can be improved through various surgical techniques. However, data is limited on the differing ability of anterior lumbar interbody fusion (ALIF), pedicle subtraction osteotomy (PSO), and transforaminal lumbar interbody fusion (TLIF) to achieve alignment goals in severely malaligned patients. PURPOSE: To examine surgical techniques aimed at restoring L4-S1 lordosis in severe adult spinal deformity (ASD). DESIGN: Retrospective review of prospectively collected data. PATIENT SAMPLE: A total of 96 patients who underwent ALIF, PSO, and TLIF were included in this study. OUTCOME MEASURES: The following data were observed for all cases: patient demographics, spinopelvic parameters, complications, and PROMs. METHODS: Severe ASD patients with preoperative PI-LL >20°, L4-S1 lordosis <30°, and full body radiographs and patient-reported outcome measures (PROMs) at baseline and six-week postoperative visit were included. Patients were grouped into ALIF (1-2 level ALIF at L4-S1), PSO (L4/L5 PSO), and TLIF (1-2 level TLIF at L4-S1). Comparative analyses were performed on demographics, radiographic spinopelvic parameters, complications, and PROMs. RESULTS: Among the 96 included patients, 40 underwent ALIF, 27 underwent PSO, and 29 underwent TLIF. At baseline, cohorts had comparable age, sex, race, Edmonton frailty scores and radiographic spinopelvic parameters (p>0.05). However, PSO was performed more often in revision cases (p<0.001). Following surgery, L4-S1 lordosis correction (p=0.001) was comparable among ALIF and PSO patients and caudal lordotic apex migration (p=0.044) was highest among ALIF patients. PSO patients had higher intraoperative estimated blood loss (p<0.001) and motor deficits (p=0.049), and in-hospital ICU admission (p=0.022) and blood products given (p=0.004) but were otherwise comparable in terms of length of stay, blood transfusion given, and postoperative admission to rehab. Likewise, 90-day postoperative complication profiles and six-week PROMs were comparable as well. CONCLUSIONS: ALIF can restore L4-S1 sagittal alignment as powerfully as PSO, with fewer intra-operative and in-hospital complications. When feasible, ALIF is a suitable alternative to PSO and likely superior to TLIF for correcting L4-S1 lordosis among patients with severe sagittal malalignment.

An Enhanced Role of Innate Immunity in the Immune Response After Kidney Transplant in People Living With HIV: A Transcriptomic Analysis.

BACKGROUND: Although kidney transplantation (KT) has become the standard of care for people living with HIV (PLWH) suffering from renal failure, early experiences revealed unanticipated higher rejection rates than those observed in HIV- recipients. The cause of increased acute rejection (AR) in PLWH was assessed by performing a transcriptomic analysis of biopsy specimens, comparing HIV+ to HIV- recipients. METHODS: An analysis of 68 (34 HIV+, 34 HIV-) formalin-fixed paraffin-embedded (FFPE) renal biopsies matched for degree of inflammation was performed from KT recipients with acute T cell-mediated rejection (aTCMR), borderline for aTCMR (BL), and normal findings. Gene expression was measured using the NanoString platform on a custom gene panel to assess differential gene expression (DE) and pathway analysis (PA). RESULTS: DE analysis revealed multiple genes with significantly increased expression in the HIV+ cohort in aTCMR and BL relative to the HIV- cohort. PA of these genes showed enrichment of various inflammatory pathways, particularly innate immune pathways associated with Toll-like receptors. CONCLUSIONS: Upregulation of the innate immune pathways in the biopsies of PLWH with aTCMR and BL is suggestive of a unique immune response that may stem from immune dysregulation related to HIV infection. These findings suggest that these unique HIV-driven pathways may in part be contributory to the increased incidence of allograft rejection after renal transplantation in PLWH.

Serious Illness Communication Tool for Palliative Care Fellows: Development, Implementation, and Lessons Learned.

Introduction: Learning expert communication skills is a core educational goal within palliative care training, yet there are few communication-based educational tools specifically designed for specialty-trained palliative care providers. Objective: To develop and implement a tool to facilitate effective learning of serious illness communication for hospice and palliative medicine fellows. Methods: A novel formative assessment tool was developed within the UCLA Palliative Care Fellowship program, and utilized throughout the academic year on a weekly basis. Focus groups were held for fellows and faculty separately at the end of the academic year in order to gain insight into the experience and effectiveness of the tool. Focus group transcripts were analyzed through thematic analysis. Results: There was a 47% participation rate in the focus groups (n = 7). Qualitative analysis demonstrated positive impact of the tool in identifying learning goals, improving quality of feedback, and in standardizing language around advanced communication skills, with most value in the first half of the fellowship year. Some aspects of the tool were found to increase feedback anxiety, including the competency scoring component, frequency of use, and utilization with individual patient encounters. Conclusion: This novel communication tool provides an important addition to serious illness communication training of specialist palliative care providers, in creating a shared mental model for naming and organizing skills, as well as generating specific high quality learning goals and feedback. Preliminary feedback from our pilot implementation phase provided important information about how to refine the tool and remove components that unnecessarily added to feedback anxiety.

Cohort profile of BIGPROMISE: a perioperative biobank of a high-risk surgical population.

PURPOSE: Postoperative complications increase mortality, disability and costs. Advanced understanding of the risk factors for postoperative complications is needed to improve surgical outcomes. This paper discusses the rationale and profile of the BIGPROMISE (biomarkers to guide perioperative management and improve outcome in high-risk surgery) cohort, that aims to investigate risk factors, pathophysiology and outcomes related to postoperative complications. PARTICIPANTS: Adult patients undergoing major surgery in two tertiary teaching hospitals. Clinical data and blood samples are collected before surgery, at the end of surgery and on the first, second and third postoperative day. At each time point a panel of cardiovascular, inflammatory, renal, haematological and metabolic biomarkers is assessed. Aliquots of plasma, serum and whole blood of each time point are frozen and stored. Data on severe complications are prospectively collected during 30 days after surgery. Functional status is assessed before surgery and after 120 days using the WHO Disability Assessment Schedule (WHODAS) 2.0. Mortality is followed up until 2 years after surgery. FINDINGS TO DATE: The first patient was enrolled on 8 October 2021. Currently (1 January 2024) 3086 patients were screened for eligibility, of whom 1750 (57%) provided informed consent for study participation. Median age was 66 years (60; 73), 28% were female, and 68% of all patients were American Society of Anaesthesiologists (ASA) physical status class 3. Most common types of major surgery were cardiac (49%) and gastro-intestinal procedures (26%). The overall incidence of 30-day severe postoperative complications was 16%. FUTURE PLANS: By the end of the recruitment phase, expected in 2026, approximately 3000 patients with major surgery will have been enrolled. This cohort allows us to investigate the role of pathophysiological perioperative processes in the cause of postoperative complications, and to discover and develop new biomarkers to improve risk stratification for adverse postoperative outcomes. TRIAL REGISTRATION NUMBER: NCT05199025.

The Hydraulic Evolution of Groundwater-Fed Pit Lakes After Mine Closure.

Open pit mining frequently requires regional water tables to be lowered to access ore deposits. When mines close, dewatering ceases allowing the water table to recover. In arid and semi-arid mining regions, the developing pit lakes are predominantly fed by groundwater during this recovery phase and pit lakes develop first into "terminal sinks" for the surrounding groundwater system. With time, the re-establishment of regional hydraulic gradients can cause pit lakes to develop into throughflow systems, in which pit lake water outflows into adjacent aquifers. In this study, we use numerical groundwater modeling to aid process understanding of how regional hydraulic gradients, aquifer properties, net evaporation rates, and pit geometry determine the hydraulic evolution of groundwater-fed pit lakes. We find that before the recovery of the regional water table to its new equilibrium, pit lakes frequently transition to throughflow systems. Throughflow from pit lakes to downstream aquifers can develop within two decades following cessation of dewatering even under low hydraulic gradients (e.g., 5 × 10-4) or high net evaporation rates (e.g., 2.5 m/year). Pit lakes remain terminal sinks only under suitable combinations of high evaporation rates, low hydraulic gradients, and low hydraulic conductivities. In addition, we develop an approximate analytical solution for a rapid assessment of the hydraulic status of pit lakes under steady-state conditions. Understanding whether pit lakes remain terminal sinks or transition into throughflow systems largely determines the long-term water quality of pit lakes and downstream aquifers. This knowledge is fundamental for mine closure and planning post-mining land use.

Exploring Clinical Remission in Moderate Asthma - Perspectives from Asia, the Middle East, and South America.

INTRODUCTION: Clinical remission is a relatively new concept in asthma but recent research initiatives suggest it could be an ambitious and achievable therapeutic target for patients with asthma. METHODS: In this modified Delphi study (comprising two online surveys, completed either side of a virtual scientific workshop), the opinions of a panel of respiratory physicians were evaluated to summarize perspective statements on key therapeutic outcomes and criteria for on-treatment clinical remission in patients with moderate asthma. An agreement threshold was pre-defined as agreement by ≥ 75% of participants. RESULTS: Surveys 1 and 2 were completed by 20 and 18 participants, respectively. Most participants (95%) agreed with the concept of clinical remission in moderate asthma and that this should be a desirable treatment goal (90%). Based on a composite measure of 4-6 desirable therapeutic outcomes, current understanding of clinical remission was considered as 12 months with no exacerbations, no oral corticosteroids, no daytime or night-time asthma symptoms (Asthma Control Test score ≥ 20 or Asthma Control Questionnaire score ≤ 0.75), stable lung function, and no treatment-related adverse events. No agreement was reached on the role of relievers in defining therapeutic outcomes or on the wider use of biomarkers and airway hyperresponsiveness for defining asthma remission in clinical practice. CONCLUSIONS: In line with recent consensus statements from the United States and Europe, there was a high level of agreement on the elements of clinical remission among a panel of respiratory physicians from Asia, the Middle East, and South America. Extension of the concept of clinical remission to patients with moderate asthma was considered aligned with the potential of clinical remission as a goal of therapy.

Mid-infrared optical coherence tomography with a stabilized OP-GaP optical parametric oscillator.

We demonstrate mid-infrared time-domain optical coherence tomography (OCT) with an orientation-patterned GaP optical parametric oscillator. Instantaneous broadband mid-infrared spectra provide reduced scattering for OCT applications including cultural heritage, quality assurance, and security. B-scan calibrations performed across the wavelength tuning range show depth resolutions of 67 µm at 5.1 µm and 88 µm at 10.5 µm. Volumetric imaging inside a plastic bank card is demonstrated at 5.1 µm, with a 1 Hz A-scan rate that indicates the potential of stable broadband OPO sources to contribute to mid-infrared OCT.