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  • A novel presurgical risk prediction model for chronic post-surgical pa

    A novel presurgical risk prediction model for chronic post-surgical pa

    Introduction

    Chronic post-surgical pain (CPSP) is known as a debilitating disease that significantly reduces quality of life and carries substantial biopsychosocial and economic consequences for both patients and society. Furthermore, low return-to-work rates and increased school absenteeism further contribute to the high socio-economic burden of chronic pain.1 Given that over 230 million people undergo surgery globally each year, with CPSP developing in 10% of surgical procedures and reaching up to 85% in certain outliers,2,3 a vast potential for CPSP is represented.4,5 Additionally, the number of surgical procedures is expected to expand with increasing obesity, inflammatory diseases and increased life expectancy. After recognizing the problem of CPSP in the 1990s, the definition underwent several modifications in recent years and many different definitions of CPSP are maintained in the literature.6–8 Recently, the definition of CPSP became more standardized after inclusion in the International Classification of Disease (ICD-11). However, since this ICD-11 definition is relatively new, its implementation is still in progress.3 The clinical success of (preventive) CPSP management remains unfortunately often unsatisfactory with persistent pain complaints and accompanying anxiety and depressive symptoms.9 In the last two decades, research on risk factors in the development of CPSP has grown significantly.2,5 Nevertheless, this has not yet led to improved postsurgical patient outcomes.9 A presurgical CPSP prediction model, suitable for daily use across a large surgical population, which has the potential to allocate high risk patients to the appropriate type of care, is urgently needed.

    Up to now, different models have been developed estimating postsurgical acute and chronic pain.10–13 However, current predictive models for CPSP often face limitations due to a narrow selection of surgical procedures, which restricts their generalizability. They also struggle with incorporating parameters from the postoperative period and rely on data that are challenging to collect in routine practice. Furthermore, many models lack robust validation, reducing their clinical utility in identifying high-risk patients across diverse surgical contexts. Additionally, the increasing adoption of the International Association for the Study of Pain (IASP) definition of CPSP raises concerns about the clinical use in cases where patients experience ongoing pain after surgery, either due to pre-existing complex pain unrelated to surgery, mixed pain conditions or minimal reductions in pain intensity post-surgically, reflecting even more its complexity.13

    Despite the complex biopsychosocial interplay of chronic pain, various surgery– and patient-related risk factors consistently emerge in the likelihood of CPSP occurrence.9 Yet, many of these factors are not easily modifiable, and others are too labor-intensive to assess effectively in a typical preoperative clinical setting. However, estimating probability of CPSP occurrence using a generalizable preoperative model could not only improve patient care and surgical outcomes by facilitating early pain management but also guide further research in the treatment of CPSP such as evaluation of pharmacological strategies in identified high-risk individuals. Moreover, CPSP prediction can have economic benefits by enhanced recovery post-surgery with early pain management and a more fluent reintegration including return to work.

    Therefore, the aim of this study was to develop a presurgical CPSP risk prediction model with good discriminative power, clinical applicability, and possible generalization to a broad group of adults undergoing different types of surgery.

    Materials and Methods

    Participants

    After approval by the Ethics Committee (BUN B3002022000112, September 2022), this single center observational pragmatic pilot study, called PERISCOPE trial, was conducted at the Antwerp University Hospital (UZA), Belgium, in accordance with the Helsinki Declaration and GCP guidelines. The protocol, including the design, of this observational pragmatic pilot study (ClinicalTrials.gov NCT05526976) has been published previously.14 Between December 2022 and September 2023, 660 Dutch-speaking adults scheduled for any type of surgery were recruited preoperatively at the tertiary Antwerp University Hospital. A written informed consent was provided by all participants prior to participation. Patients were excluded if one of the following was present: age below 18 years, not able to complete questionnaires, (diagnostic) procedures without scheduled intervention (such as bronchoscopy, hysteroscopy, gastroscopy, and colonoscopy), or informed consent refusal. Included patients received an analgesic regimen prescribed for postoperative pain by the attending anesthesiologist according to the surgery-specific anesthesia guidelines as performed in our center.

    Study Design, Data Collection and Outcome Variable

    During the study duration, there were no deviations from the standard of care nor additional interventions were executed. This study followed the Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis (TRIPOD) guidelines for prediction model development.15,16

    Patient‐reported data acquired at screening visit, post-surgery day 1, month 1 and month 3 were collected electronically (REDCAP®, Research Electronic Data Capture, Version 13.6.1, Vanderbilt University, Nashville, Tennessee, USA). During the screening visit, the socio-demographic characteristics (age, sex, level of education and BMI) of all participants, as well as their medical history, preoperative analgesic usage and surgical details were recorded and verified through the electronic medical record. Additionally, participants were instructed in the pain assessment that would be conducted throughout the study trajectory. Participants were asked to electronically complete the following patient-reported outcome measurements (PROMs) at three different timepoints (before surgery, 1 month and 3 months after surgery): surgical-site pain intensity (11-level numeric rating scale (NRS)),17 health-related quality of life (EQ-5D-5L),18 patient experienced level of depression and anxiety (Hospital Anxiety and Depression Scale (HADS) and Spielberger’s Trait Anxiety Inventory (STAI-trait).19–21 Herewith, experienced concerns about the surgery were assessed considering its prevalence in daily practice and suggested opportunity for future intervention.9,21–23 When, pain intensity was scored above two on the 11-level NRS, pain assessment was extended with a screening for neuropathic pain characteristics (Douleur Neuropathique questionnaire (questionnaire part of the DN4)24 and a validated self-report of pain impact on life (Multidimensional Pain Inventory (MPI) part 125). Additionally, a modified version of Kalkman and Althaus index, which previously showed good predictive properties, was assessed presurgical.26,27

    Acute postoperative pain intensity (NRS) on post-surgery day 1 was registered as an additional timepoint. A condensed version of the study design is illustrated in Figure 1. To minimize follow-up non-compliance, up to five reminders were sent via Email and telephone. During follow-up contacts changes in medication, diagnosed surgical complications and visits to the general practitioner/psychologist/surgeon/pain physician were logged.

    Figure 1 Study design. Perioperative patients flow with indicated times when questionnaires were asked to be filled in.

    The objective of this study was to develop a presurgical CPSP risk prediction model useful for clinical practice, with a generalizability to a variety of surgical procedures. The outcome parameter of interest for CPSP was defined as the pain intensity localized at the surgical field of ≥3 on NRS, three months post-surgery.

    Candidate Predictors

    Based on clinical knowledge and a review of the literature, we identified 33 candidate predictors (comprehensive list available in Appendix 1). Within this predictors group, we considered sociodemographic characteristics including sex, age, BMI and educational level (low (no secondary education)/intermediate (secondary education)/high (higher education)), presurgical analgesic consumption (Yes/No, opioids and antineuropathics), surgical procedure and the above mentioned PROMs (modified version of Kalkman and Althaus, NRS, EQ-5D-5L, HADS, STAI).18,19,26–28

    The 44 different executed surgical procedures across 11 disciplines were categorized by 3 independent pain physicians into six categories according to the Kalkman classification: Ophthalmology, Laparoscopy, Ear-nose throat (ENT) surgery, Orthopedic surgery, Laparotomy and Other surgeries.26 Furthermore, the procedures were classified into the following categories: small procedures with high risk, large procedures with high risk, and other, as outlined in the protocol.14 Additionally, these surgical procedures were divided into a categorization using 7 categories (Surgical-7 categorization) as an alternative to the Kalkman classification.

    Sample Size Calculation

    A logistic regression model has been developed to predict the probability of CPSP 3 months post-surgery. The estimated probability from this model was then used to construct a ROC curve (receiver operating characteristic) to discriminate between CPSP and non-CPSP and determine the optimal cut-off risk value regarding maximal sensitivity and specificity.

    The sample size calculation was based on constructing a 95% confidence interval for the area under the ROC curve (AUC). A width of 0.2 and assuming an AUC of 0.7 showed the need for at least a group of 56 CPSP-patients.29 Based on the available scientific evidence at the time of study design, considering a possible mixed CPSP incidence of 10%, we needed a minimum inclusion of 560 patients scheduled for surgery. Taking subject withdrawal, incomplete data or lost to follow-up into account, a total of 660 patients were recruited.

    Statistical Analysis

    Numeric variables are summarized with mean and standard deviation or median and interquartile range and categorical variables with observed frequency and percentage. An initial logistic regression model was fitted with Kalkman score and modified Althaus as predictors and CPSP as outcome. Given a multivariable model with all predictors was not possible (only 80 cases), a stepwise forward approach was followed to build the prediction model. Starting with univariable models evaluating all 33 candidate predictors, the predictor resulting in the best model in terms of highest AUC and significance was then retained. In the next step, multivariable models with 2 predictors are considered, keeping in each model the best univariable candidate and adding one of the other candidate predictors. Overlapping candidates were left out (eg, different instances of pain, different instances or surgery). These steps are repeated for multivariable models with 3 (keeping the 2 best candidates from the previous model fixed and adding one extra candidate) and 4 predictors leading to a final model. The ROC curve of the final model is then compared with the ROC curve of the initial model using a DeLong’s test for correlated ROC curves. Bootstrap techniques were used to evaluate the model’s performance in similar future patients. Random bootstrap samples were drawn with replacement (100 replications) from the data set consisting of all patients who filled in the Kalkman and modified Althaus questionnaire preoperatively and the NRS score at month 3 (n = 415). Forward selection of the candidates was repeated within each bootstrap sample. This allowed us to adjust the estimated model performance and regression coefficients for overoptimism or overfitting. A calibration plot was constructed to examine the agreement between the predicted probabilities and the observed frequencies and calibration measures (Expected/Observed) E/O ratio, calibration slope and calibration in the large (CITL) are reported.

    A complete case analysis on n = 415 patients was used per considered model (if a patient has missings in a variable not included in the model, the patient contributed to the considered model) (Figure 2). No single candidate predictor had missing values >5%. As the outcome was missing in 16% of 496 patients, multiple imputation was considered with 50 imputed datasets and model selection and bootstrap validation were repeated on the imputed datasets.

    Figure 2 Flowchart of sample cohort for analysis.

    All analyses were performed with the statistical software R version 4.3.1. except the bootstrap validation of the final model which was done in Stata version 18.5. Multiple imputation was done with the R-packages MICE and psfmi was used for model estimation, pooling and validation after imputation.

    Results

    Patient Demographics and Characteristics

    In this pilot study, 660 patients were included. Of the 660 recruited subjects, 164 were excluded from analysis due to preoperative factors (24.8%). Of the 496 subjects having preoperative data, 81 were excluded due to postoperative factors (16.3%). Figure 2 summarizes the study sample cohort for analysis. Table 1 provides descriptive statistics for the 415 patients at the screening visit. These 415 patients underwent 44 different operations in 11 disciplines. Three months post-surgery 19.3% of the surveyed subjects reported a pain NRS score ≥3 at the surgical site (Figure 3).

    Table 1 Descriptive Statistics at Screening Visit

    Figure 3 Overview of the distribution of pain intensity (NRS) at the surgical site area three months post-surgery.

    Development of a New Predictive Model

    The initial model with Kalkman score (p < 0.0001) and Althaus risk index (p = 0.074) as predictors for CPSP, results in an AUC of 0.72 (95% CI [0.66,0.78]). From the univariable models with each of the 33 predictors, several predictors are significant where highest AUCs are obtained for the preoperative pain questions (NRS q1 (p < 0.001), q2 (p < 0.001) and Kalkman preoperative pain (p < 0.001)), respectively, 0.76, 0.77 and 0.76). Next, the 30 predictors (leaving out NRS q2 and Kalkman preoperative pain as they are also pain variables) were now added to the model with NRS q1. This model with two predictors led to the highest AUC of 0.80 when including Kalkman surgery (p = 0.001) besides NRS q1. As the category Ophthalmology is very small the Kalkman surgery is from now on recategorized into five categories with Ophthalmology and Other as one category. In the next step evaluating a model with three predictors including the concern question “I am worried about the procedure” (p = 0.032) is retained with an AUC of 0.81. Finally, a model with four predictors adding Education (p = 0.047) as fourth variable gives an AUC of 0.81 (95% CI [0.76,0.87]). Comparing the final model with the four predictors NRS q1, surgery, concern question and education to the initial model with Kalkman score and Althaus risk index gives a p-value of 0.0003 (DeLong’s test) showing a significant improvement (higher AUC) of the final model to this initial model. Together, these four questions form the Persistent Post-surgical Pain Prediction (P4)-Prevoque™ questionnaire (Table 2).

    Table 2 Final Model for Presurgical CPSP Prediction: PrevoqueTM Questionnaire

    Bootstrap was used to adjust for overfitting and the AUC of the final model was 0.76 (overoptimism 0.05). The odds (adjusted for overfitting) on CPSP were 27% higher when the pre-operative pain score goes up 1 unit on the 11-level scale. ENT surgery has the smallest odds on CPSP, and abdominal surgery has more than 8 times higher odds on CPSP compared to ENT, other and ophthalmic surgery 6 times higher odds compared to ENT, orthopedic surgery more than 4 times and laparoscopic surgery 2.5 times higher compared to ENT. The odds on CPSP were 19% higher when the answer on “I worry about the operation” goes up with one unit. The patients with low education level have an almost 3 times higher odds on CPSP compared to intermediate and high education level. The predicted probabilities using the regression coefficients adjusted for overfitting in the final model were then calculated. According to the Youden index the ideal cutoff on these predicted probabilities is 23.9% resulting in a sensitivity of 69.7% and specificity of 82.0%. Using the closest in the top left corner method, a cutoff of 20.58% is chosen resulting in a sensitivity of 73.7% and a specificity of 77.0%. Figure 4 displays the calibration plot of the observed outcomes versus the predicted outcomes with the performance measures E/O ratio, calibration slope and calibration in the large where we see a slight tendency that estimates are a bit too high for individuals at high risk, and too low for those at low risk but overall calibration measures are fair.

    Figure 4 Calibration plot for validation of the proposed prediction model.

    Pooling and selecting the logistic regression models of the 50 imputed datasets revealed a similar model with the same 4 predictors. Internal validation across the imputed datasets with bootstrapping resulted in an optimism corrected AUC of 0.76 (95% CI [0.67,0.82]). Optimism corrections were larger for calibration results.

    Discussion

    This study presents the development of a presurgical CPSP prediction model for adults undergoing a wide range of surgical procedures. Prediction models are being developed to help healthcare providers estimate the likelihood of a particular event occurring so that they can adjust their decisions accordingly.30 So far, various models have been created in recent years to predict postsurgical pain. However, to date, no generalizable CPSP risk stratification model independent for type of surgery is extensively applied. Our multivariable developed model, P4-Prevoque™ questionnaire, can presurgical classify adults undergoing a scheduled surgical procedure, forecasting an individual likelihood of CPSP based on four pre-operative patients’ characteristics: preoperatively pain score at the surgical area (0 to 10 on NRS) [1], the type of surgery (in 5 categories) [2], education level (in 3 levels) [3] and concerns reported about the planned surgical procedure (in 6 levels) [4]. Model performance is good in terms of discriminative power and calibration meaning the model is a useful tool for detecting CPSP.31

    In our single center study cohort, 19.3% of the included patients reported a pain intensity of more than 2 to 10, three months after surgery. Although this finding falls within the broad spectrum of reported CPSP incidence, this average may still be considered comparatively high.3,5,9,32,33 Type of surgery is a known contributing factor to the substantial incidence variation.9 Moreover, this high mean incidence in our study cohort may be indicative of the tertiary hospital surgical procedures and population. Additionally, the inconsistent application of CPSP-definitions may serve as a confounding factor. Since the ICD-11 definition is relatively recent and implementation is ongoing, it is important to note that many different definitions are still maintained in the literature as described by Glare et al.34 In a supplementary analysis, the most recent definition of CPSP as outlined in the ICD-11 defining CPSP as an increase in NRS score of 1 or more at 3 months post-surgery compared to preoperative values was considered for the subjects who had an increase in pain intensity at month 3 compared to pre-surgery.3 This resulted in a group of 72 CPSP patients according to ICD-11 definition. Of those 72 patients, 29 had CPSP both according to the ICD-11 definition and the primary outcome variable. Furthermore, a second predictive model analysis for this subsequent outcome variable was executed. This included presurgical pain intensity at the surgical area (11-level NRS), type of surgery (Surgery-7 classification) and STAI trait and is as such similar to the proposed primary model. Despite the necessity for uniformity in definition, we acknowledge the concerns raised in the recent publication by Papadomanolakis-Pakis et al regarding the ICD-11 definition. Specifically, patients with stable or reduced pain levels are not classified as CPSP by the ICD-11 definition, highlighting the need for pain assessment in educated patients or clinical confirmation in the diagnosis of CPSP.13 Furthermore, patients exhibiting the maximum indicated pain score preoperatively are unable to report a higher score on the NRS post-surgery, thereby rendering them ineligible for the diagnosis of CPSP under this definition. This CPSP definition, in response to the need for a scientifically rigorous and practically applicable framework, is likely to evolve over the next few years. It may also incorporate considerations regarding the impact of analgesic use and changes in pain type within its diagnostic criteria.

    Presurgical pain is found to be a strong predictor in our proposed model. This finding is in line with literature that the presence of persistent nociceptive stimulation may cause pain physiology changes leading to a sensitized nervous system.35,36 Also, the predictive role of surgical type is in accordance with previous literature as surgical tissue trauma, surgery duration and neuronal damage are important contributing factors.9 Furthermore, a recent meta-analysis by Giusti evaluated psychosocial predictors for CPSP and concluded that a heterogeneous group of psychological predictors are significantly associated with CPSP.22 In this study, concerns about the surgery, and anxiety and depression as identified psychosocial predictors were assessed. Worrying about the planned surgical procedure as a single question answer appears to be more predictive than anxiety or depressive states in this study cohort.

    As mentioned, during recent years, a handful of prognostic models have been developed on postoperative pain intensity.10,13,32,37 Two existing prediction models identified as potentially useful in daily practice were incorporated in this research and compared with our prediction model.26,27 However, the Althaus risk index was specifically developed to predict pain 6 months post-surgery and included post-surgical acute pain as a predictor (although a version of the model without this variable is also presented in their publication).27 Similarly, the Kalkman score focused on the presence of severe postoperative pain within the first hour following surgery as the outcome.26 Consequently, these models differ in their outcomes and are therefore not entirely comparable. Notwithstanding, the modified version of Kalkman and Althaus risk index (without the post-surgical acute pain item) was assessed preoperatively, and logistic model evaluation resulted in an AUC of 0.72. Comparatively, the developed prediction model resulted in an AUC of 0.81. Both ROC curves were then compared with a DeLong’s test for correlated ROC curves leading to a p-value of 0.0003 showing the significant improvement of the AUC of our model. Our findings suggests that both the Kalkman score and the Althaus index are effective presurgical prediction models for CPSP, although they were not used in this study for the intended outcome or at the appropriate timepoint. However, the P4-Prevoque™ model, as designed, demonstrates greater accuracy and significantly enhanced predictive power compared to the two previously mentioned models.

    A comparison with even more recently developed prediction models11,12,38 is not feasible due to substantial differences in the study populations and outcome variables including varying interpretations and applications of CPSP definition, timing and the selection of predictors. Beyond the similarities and differences between the P4-Prevoque™ model and the few existing alternatives, the proposed P4-Prevoque™ model distinguishes itself by its inclusive nature, enhancing its generalizability. Our objective was to design a risk model for CPSP that is both clinically relevant and suitable for widespread implementation, by reducing the number of questionnaires and categorizing the responses in a manner conducive to preoperative screening visits, telephone consultations, and digital preoperative care pathways. The P4-Prevoque™ questionnaire facilitates a rapid assessment of the risk for developing CPSP or transitioning to a more severe pain condition. It offers multiple applications for vulnerable patients scheduled for surgery, enhancing patient allocation in research trials, informing tailored management strategies, and ultimately improving their comprehensive postoperative outcomes.

    The potential benefit in reducing the incidence of CPSP using a prediction model, to date, still remains unclear.9–13 Nevertheless, CPSP as a complex biopsychosocial phenomenon with an often challenging treatment approach could benefit from an early, presurgical patient-centered care.9,22,34,39 Early identification of individuals at risk for developing CPSP is essential to ensure prompt assignment to the appropriate care. Subsequently, it will have to be investigated whether early non-pharmacological and pharmacological approaches in at-risk subjects planned for various types of surgery could result in CPSP incidence reduction.9,40,41

    Thereafter, decision analysis methods can be used to assess whether a prediction model should be used in practice by incorporating and quantifying its clinical impact, considering the anticipated benefits, risks, and costs. Furthermore, this study focuses on CPSP three months after surgery. Between three and six months postoperatively, pain complaints may fluctuate in terms of prevalence, intensity, and clinical relevance. As a result, prediction models targeting outcomes at three and six months may differ. Yet, by targeting the three-month outcome, we aim to identify patients early, when there is a meaningful opportunity for intervention.

    In addition to the described strengths, our study has several limitations. First, only 415 out of 660 patients completed questionnaires, resulting in a considerable amount of missing data. Comparisons between completers and non-completers on sex, age, BMI, education and surgery type only showed a significant difference in education level. Thirty percent of non-completers had a high education level compared to 45% of completers. This is an important group missing in the analysis, already known for previously identified patient-related risk factors. Besides that, the small sample size also prohibited a backward selection procedure in the model building step. Another potential limitation is the probability of misclassification of the endpoint CPSP. Similar to others, in this pragmatic study, postoperative in-person follow-up visits were not conducted.11,13 Participants underwent remote pain assessments, after education during the screening visit. Diagnosed surgical complications and readmissions were verified via telephone and cross-checked with the medical records. However, the lack of a physical examination to thoroughly assess the characteristics of CPSP might be point of discussion as reported in recent research.33 Finally, no detailed assessment of the presurgical pain complaints was performed. This could affect the excitability of a nervous system such as in preexisting nociplastic pain syndromes as described by Fitzcharles et al.42

    In recent years, more research has addressed machine learning (ML) models. Langford and colleagues43 reviewed the use of ML to predict postoperative pain and opioid use, highlighting the growing potential of these methods to improve early risk identification. They emphasized the need for rigorous methodological standards and validation to ensure clinical applicability. These findings support the relevance of our approach in developing a robust and interpretable CPSP prediction model.

    Conclusion

    In conclusion, using the designed model, the occurrence of CPSP can be presurgical estimated in adults scheduled for surgery with a sensitivity of 74% and specificity of 77% in the studied population. The P4-Prevoque™ model, composed of four questions, can be easily obtained and has the potential to seamlessly integrate into preoperative workflows through digital tools such as online forms and mobile apps, as well as during in-person visits via kiosks in waiting areas or at healthcare providers’ offices, supporting both modern and traditional care approaches. Future research should prioritize the external validation of the prediction model using an independent dataset, its evaluation in non-university hospital surgical settings, and subsequently its implementation and valorization. If CPSP-at risk subjects can be identified early, preventive pharmacological and non-pharmacological antinociceptive interventions may be reconsidered. Given the relative immutability of surgery type and educational level, we argue that research and prevention efforts should concentrate not only on pain but also on the psychological aspects, such as patient fear, anxiety, and concerns about the surgical procedure. Following prediction model validation, it is important to evaluate its impact on patient-reported outcome measures and patient-reported experience measures. Ultimately, it remains to be determined whether and which interventions targeting high-risk individuals will lead to a reduction in the burden of CPSP.

    Data Sharing Statement

    Requests for (de-identified) raw data used in this clinical trial can be directed to the corresponding author.

    Acknowledgments

    This research has been conducted with screening at the preoperative screening anesthesiology department. We would like to thank the staff, especially Dr H Vandervelde, for their contributions.

    Author Contributions

    All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

    Funding

    No funding was obtained for this research project.

    Disclosure

    The authors declare that they have no conflicts of interest in this work.

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    29. Hajian-Tilaki K. Sample size estimation in diagnostic test studies of biomedical informatics. J Biomed Inform. 2014;48:193–204. doi:10.1016/j.jbi.2014.02.013

    30. Moons KGM, Royston P, Vergouwe Y, Grobbee DE, Altman DG. Prognosis and prognostic research: what, why, and how? BMJ. 2009;338(feb23 1):b375–b375. doi:10.1136/bmj.b375

    31. de Hond AAH, Steyerberg EW, van Calster B. Interpreting area under the receiver operating characteristic curve. Lancet Digit Health. 2022;4(12):e853–e855. doi:10.1016/S2589-7500(22)00188-1

    32. Fletcher D, Lavand’homme P. Towards better predictive models of chronic post-surgical pain: fitting to the dynamic nature of the pain itself. Br J Anaesth. 2022;129(3):281–284. doi:10.1016/j.bja.2022.06.010

    33. Martinez V, Lehman T, Lavand’homme P, et al. Chronic postsurgical pain A European survey. Eur J Anaesthesiol. 2024;41(5):351–362. doi:10.1097/EJA.0000000000001974

    34. Glare P, Aubrey KR, Myles PS. Transition from acute to chronic pain after surgery. Lancet. 2019;393(10180):1537–1546. doi:10.1016/S0140-6736(19)30352-6

    35. Nijs J, George SZ, Clauw DJ, et al. Central sensitisation in chronic pain conditions: latest discoveries and their potential for precision medicine. Lancet Rheumatol. 2021;3(5):e383–e392. doi:10.1016/S2665-9913(21)00032-1

    36. Feizerfan A, Sheh G. Transition from acute to chronic pain. Continuing Educ Anaesth Crit Care Pain. 2015;15(2):98–102. doi:10.1093/bjaceaccp/mku044

    37. Papadomanolakis-Pakis N, Haroutounian S, Christiansen CF, Nikolajsen L. Prediction of chronic postsurgical pain in adults: a protocol for multivariable prediction model development. BMJ Open. 2021;11(12):e053618. doi:10.1136/bmjopen-2021-053618

    38. Montes A, Roca G, Cantillo J, Sabate S. Presurgical risk model for chronic postsurgical pain based on 6 clinical predictors: a prospective external validation. Pain. 2020;161(11):2611–2618. doi:10.1097/j.pain.0000000000001945

    39. Katz J, Weinrib A, Fashler S, et al. The Toronto General Hospital Transitional Pain Service: development and implementation of a multidisciplinary program to prevent chronic postsurgical pain. J Pain Res. 2015;695. doi:10.2147/JPR.S91924

    40. Carley ME, Chaparro LE, Choinière M, et al. Pharmacotherapy for the prevention of chronic pain after surgery in adults: an updated systematic review and meta-analysis. Anesthesiology. 2021;135(2):304–325. doi:10.1097/ALN.0000000000003837

    41. Chaparro LE, Smith SA, Moore RA, Wiffen PJ, Gilron I. Pharmacotherapy for the prevention of chronic pain after surgery in adults. Cochrane Database Syst Rev. 2013;2021(6). doi:10.1002/14651858.CD008307.pub2

    42. Fitzcharles MA, Cohen SP, Clauw DJ, Littlejohn G, Usui C, Häuser W. Chronic pain 2 nociplastic pain: towards an understanding of prevalent pain conditions. Lancet. 2021;397(10289):2098–2110. doi:10.1016/S0140-6736(21)00392-5

    43. Langford DJ, Reichel JF, Zhong H, et al. Machine learning research methods to predict postoperative pain and opioid use: a narrative review. Reg Anesth Pain Med. 2025;50(2):102–109. doi:10.1136/rapm-2024-105603

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  • CM grieved over loss of lives in Muzaffargarh traffic accident

    CM grieved over loss of lives in Muzaffargarh traffic accident

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    LAHORE, Jul 05 (APP):Punjab Chief Minister Maryam Nawaz Sharif on Saturday expressed deep sorrow and grief over the tragic loss of precious human lives in a traffic accident involving a collision between a trailer and a passenger bus near Muzaffargarh.

    The CM extended her heartfelt condolences to the bereaved families and prayed for the departed souls.

    She also expressed sympathy with the injured and directed the administration to ensure they receive the best possible medical treatment without delay.

    CM Maryam Nawaz said that the Punjab government is committed to enhancing road safety and preventing such tragic incidents in the future through improved traffic regulations and strict enforcement measures.

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  • Better Artificial Intelligence (AI) Stock: SoundHound AI vs. C3.ai

    Better Artificial Intelligence (AI) Stock: SoundHound AI vs. C3.ai

    • SoundHound AI and C3.ai are pure-play artificial intelligence (AI) software companies with massive opportunities ahead.

    • SoundHound AI stock is more richly valued than C3.ai, but may have a greater runway for growth ahead.

    • Choosing between the two stocks may ultimately boil down to the risk tolerance levels of investors.

    • 10 stocks we like better than SoundHound AI ›

    The adoption of artificial intelligence (AI) software is increasing at an incredible pace because of the productivity and efficiency gains this technology is capable of delivering, and the good part is that this niche is likely to sustain a healthy growth rate over the long run.

    According to ABI Research, the AI software market is expected to clock a compound annual growth rate (CAGR) of 25% through 2030, generating $467 billion in annual revenue at the end of the decade. That’s why it would be a good time to take a closer look at the prospects of SoundHound AI (NASDAQ: SOUN) and C3.ai (NYSE: AI) — two pure-play AI companies that could help investors capitalize on a couple of fast-growing niches within the AI software market — and check which one of them is worth buying right now.

    Image source: Getty Images.

    SoundHound AI provides a voice AI platform where its customers can create conversational AI assistants and voice-based AI agents that can be deployed for multiple uses, such as taking orders in restaurants, car infotainment systems, and customer service applications, among others.

    This particular market is growing at a nice clip, as deploying AI-powered voice solutions can help companies improve productivity and efficiency, since they will be able to automate tasks. Companies can now significantly improve their customer interaction experiences, thanks to the availability of round-the-clock multilingual AI agents and assistants.

    Not surprisingly, SoundHound AI has been witnessing a robust growth in demand for its voice AI solutions, which explains the solid revenue growth in the past year.

    SOUN Revenue (TTM) Chart

    SOUN Revenue (TTM) data by YCharts.

    But here’s what investors should look forward to: The conversational AI market could grow at an annual average rate of almost 24% through 2030, generating over $41 billion in annual revenue by the end of the decade. SoundHound AI has been growing at a much faster pace than the overall market, suggesting it is gaining a bigger share of this lucrative space.

    SoundHound’s revenue guidance of $167 million at the mid-point for 2025, is nearly double the revenue it reported last year. Importantly, its cumulative subscriptions and bookings backlog stood at a massive $1.2 billion last year. This metric is a measure of the potential revenue that the company expects to “realize over the coming several years,” suggesting it can maintain its healthy growth rates for a long time to come thanks to the AI-fueled opportunity it’s sitting on.

    C3.ai is a pure-play enterprise AI software platform provider that enables its customers to build generative AI applications and agentic AI solutions. The company claims that it provides 130 comprehensive enterprise AI applications ready for deployment across industries such as oil and gas, manufacturing, financial services, utilities, chemicals, defense, and others.

    It has been in the news of late for receiving a bigger contract worth $450 million from the U.S. Air Force for maintaining aircraft, ground assets, and weapons systems for the next four years. However, this is just one of the many contracts that the company has been landing lately.

    C3.ai’s offerings are used across diverse industries, and its customer base includes the likes of Baker Hughes, which recently expanded its partnership with the company; local and state government bodies across multiple U.S. states; and companies such as Ericsson, Bristol Myers Squibb, Chanel, and others. The company’s fast-expanding customer base and the bigger contracts that it is signing with existing customers explain why there has been an uptick in C3.ai’s growth of late.

    AI Revenue (TTM) Chart

    AI Revenue (TTM) data by YCharts.

    The company finished fiscal 2025 (which ended on April 30) with a 25% increase in its revenue to $389 million. Management expects another 20% increase in total revenue in fiscal 2025. Consensus estimates suggest that C3.ai is likely to report similar growth next year, followed by an acceleration in fiscal 2028.

    AI Revenue Estimates for Current Fiscal Year Chart

    AI Revenue Estimates for Current Fiscal Year data by YCharts.

    There’s a strong possibility, however, that C3.ai will exceed expectations and its own forecast for growth this year. That’s because C3.ai ended the previous fiscal year with 174 pilot projects, which it calls initial production deployments. The good part is that the company has been converting its pilots into contracts at a healthy rate.

    C3.ai turned 66 of its initial production deployments into long-term contracts in fiscal 2025. The company ended fiscal 2024 with 123 pilot projects, which means that it has a conversion rate of more than 50%. So the robust increase in the company’s pilot projects last year means that it could close more such initial production deployments into full agreements in the current fiscal year, going by past trends.

    So there is a strong possibility of C3.ai’s growth rate exceeding Wall Street’s expectations, which should ideally turn out to be a tailwind for its stock price in the long run.

    While it is clear both SoundHound and C3.ai are growing at a nice pace because of AI, the former’s growth rate is much higher. However, to buy SoundHound stock, investors will have to pay a handsome price-to-sales ratio of nearly 38. C3.ai, on the other hand, is trading at a much more attractive 8 times sales, which is almost in line with the U.S. technology sector’s average sales multiple.

    So, investors looking for a mix of steady growth and attractive valuation can consider buying shares of C3.ai. However, if you have a higher appetite for risk and are willing to pay for a stock with a richer valuation, then consider buying SoundHound AI, as its faster growth could help it clock more upside, though the expensive valuation also exposes it to more volatility.

    Before you buy stock in SoundHound AI, consider this:

    The Motley Fool Stock Advisor analyst team just identified what they believe are the 10 best stocks for investors to buy now… and SoundHound AI wasn’t one of them. The 10 stocks that made the cut could produce monster returns in the coming years.

    Consider when Netflix made this list on December 17, 2004… if you invested $1,000 at the time of our recommendation, you’d have $699,558!* Or when Nvidia made this list on April 15, 2005… if you invested $1,000 at the time of our recommendation, you’d have $976,677!*

    Now, it’s worth noting Stock Advisor’s total average return is 1,060% — a market-crushing outperformance compared to 180% for the S&P 500. Don’t miss out on the latest top 10 list, available when you join Stock Advisor.

    See the 10 stocks »

    *Stock Advisor returns as of June 30, 2025

    Harsh Chauhan has no position in any of the stocks mentioned. The Motley Fool has positions in and recommends Bristol Myers Squibb. The Motley Fool recommends C3.ai. The Motley Fool has a disclosure policy.

    Better Artificial Intelligence (AI) Stock: SoundHound AI vs. C3.ai was originally published by The Motley Fool

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  • Thompson defies injury for Wimbledon breakthrough – ATP Tour

    1. Thompson defies injury for Wimbledon breakthrough  ATP Tour
    2. Thompson marks Wimbledon career milestone, Hijikata out after bad light drama  The Sydney Morning Herald
    3. Around The Grounds: Day 5  Wimbledon
    4. Aussie seals huge career-first amid dramatic scenes for Wimbledon fan favourite  Yahoo
    5. Thommo time: Aussie star produces Wimbledon masterclass as erratic Alcaraz survives  Fox Sports

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  • Type 2 diabetes mellitus with chronic kidney disease benefits from long-term restriction of dietary protein intake: a 10-year retrospective cohort study | BMC Nutrition

    Type 2 diabetes mellitus with chronic kidney disease benefits from long-term restriction of dietary protein intake: a 10-year retrospective cohort study | BMC Nutrition

    Results of the T2DM with CKD cohort

    Baseline data characteristics

    As demonstrated in Supplementary Fig. 1, which outlines the pre-PSM screening process, 856 patients were preliminarily assessed, with 36 subsequently excluded. Exclusions were 21 cases of co-infection, 10 cases of concomitant malignant tumors, and 5 patients with thyroid disease or cirrhosis. Ultimately, 820 patients were included in the final analysis. Over an average follow-up period of 33.36 months, 277 patients reached the study endpoint (initiation of dialysis, progression to ESRD, renal transplant, serum creatinine doubling, cardiovascular and cerebrovascular diseases). These included 172 patients who progressed to ESRD, 58 patients with a 50% decline in eGFR from baseline, and 47 patients who experienced major cardiovascular or cerebrovascular events.

    PSM analysis of the T2DM with CKD cohort

    As shown in Supplementary Fig. 2, variables matched using propensity scores included key clinical characteristics such as sex, age, baseline SCr, and UACR. Matching was performed in a 1:1:1 ratio with a caliper value of 0.2. The balance of propensity scores across the three dietary regimen groups was evaluated using a multi-balance test.

    Following 1:1:1 matching, a total of 168 patients were divided into three groups with different DPIsUCR levels in the final analysis, as shown in Fig. 1. After an average follow-up period of 32.94 months, 53 patients reached the study endpoint. Among them, 34 progressed to end-stage renal disease, 13 experienced a 50% reduction in eGFR from baseline, and 6 had cardiovascular or cerebrovascular events. The enrollment process is detailed in Fig. 1.

    In the original cohort, baseline characteristics such as gender, age, and eGFR showed significant differences among the three groups. However, after matching, these differences were balanced, as detailed in Table 1. For instance, the baseline ages of the three groups were [57.50 (50.00, 63.00) vs. 57.00 (51.75, 62.00) vs. 55.50 (50.50, 62.00) years, P = 0.672], and baseline renal function (eGFR) values were [46.89 (34.15, 73.23) vs. 55.85 (37.70, 79.26) vs. 51.98 (34.80, 90.05) ml/min/1.73 m², P = 0.548]. Other baseline characteristics also achieved balance.

    Table 1 Demographic and biochemical characteristics of enrolled T2DM with CKD patients before and after propensity score matching

    Baseline utilization rates of renoprotective medications were comparable across CKD stages (Table 1). Among patients with CKD stages 1–3, RAS inhibitors (RASi) were the most commonly prescribed medications, followed by SGLT2 inhibitors (SGLT2i), mineralocorticoid receptor antagonists (MRAs), and GLP-1 receptor agonists (GLP-1 analogues), both before and after PSM. In CKD stage 4, the proportions of medication use were similar. Statistical comparisons revealed no significant differences in medication use between CKD stages 1–3 and stage 4 (all p > 0.05; Chi-square tests).

    Fig. 1

    Flowchart of patients in the T2DM with CKD cohort after propensity score matching. Abbreviation: DPIsUCR dietary protein intake based on sUCR equation

    Real-world prognosis analysis of DPIsUCR formula in T2DM with CKD cohort

    In the matched cohort, we used the Kaplan-Meier curve to assess the relationship between three different DPIsUCR levels and all-cause mortality. As shown in Fig. 2a, the survival curve for patients in the LPD group (DPIsUCR <0.8 g/kg·d), calculated using the DPIsUCR formula, was superior to that of the higher-protein diet group (DPIsUCR >1.0 g/kg·d). Additionally, Fig. 2b illustrates that for CKD stages 3–4 patients, the survival curve for the low-protein diet group (DPIsUCR <0.8 g/kg·d) remained better over time compared to the higher-protein group (DPIsUCR >1.0 g/kg·d), with statistically significant results. To assess whether significant survival differences existed among patients in different dietary protein groups (based on DPIsUCR), we performed both univariate and multivariate Cox regression analyses (Supplementary Table 1). The univariate Cox analysis revealed that, compared to patients with DPIsUCR >1.0 g/kg·d, those with DPIsUCR <0.8 g/kg·d had a 44% lower risk. After adjusting for age, sex, smoking history, SBP, HbA1c, Alb, UA, LDLC, and eGFR in the multivariate Cox regression analysis, the risk for patients with DPIsUCR <0.8 g/kg·d was reduced by 54% compared to those with DPIsUCR >1.0 g/kg·d.

    After PSM, patients with DPIsUCR <0.8 g/kg·d had a 56% lower risk of reaching the endpoint compared to those with DPIsUCR >1.0 g/kg·d in the univariate Cox analysis. With further adjustments for age, sex, smoking history, HbA1c, eGFR, UA, and LDLC in the multivariate Cox analysis, the risk for patients with DPIsUCR <0.8 g/kg·d was reduced by 63% compared to those with DPIsUCR >1.0 g/kg·d.

    Subgroup analysis

    In this study, we explored heterogeneity by conducting subgroup analyses of both original and propensity score-matched cohorts. As illustrated in Fig. 3(a-b), subgroup analyses were stratified by gender, age, comorbidities, SBP, HbA1c, Alb, UACR, eGFR, DPIsUCR, and other indicators, integrating results from univariable Cox analyses (Supplementary Table 1) with clinical risk factors. Before matching, subgroups with significantly lower risks (HR < 1) included: Female patients (HR 0.70, 95% CI 0.53–0.91; p = 0.009), Age ≥ 60 years (HR 0.69, 95% CI 0.51–0.92; p = 0.012) and Alb ≥ 30 g/L (HR 0.57, 95% CI 0.40–0.80; p = 0.001). Subgroups with elevated risks (HR > 1) were: UACR ≥ 300 mg/g (HR 2.79, 95% CI 1.97–3.95; p < 0.001), eGFR 30–59 ml/min/1.73 m² (HR 1.71, 95% CI 1.23–2.23; p = 0.002), eGFR < 30 ml/min/1.73 m² (HR 5.54, 95% CI 3.79–8.10; p < 0.001) and DPIsUCR >1.0 g/kg·d (HR 1.48, 95% CI 0.91–2.41; p < 0.001). After matching, the risk associations were further refined. Protective subgroups (HR < 1) were: Female (HR 0.29, 95% CI 0.13–0.67; p = 0.004) and Alb ≥ 30 g/L (HR 0.35, 95% CI 0.15–0.82; p = 0.015). High-risk subgroups (HR > 1) were: HbA1c ≥ 7.0% (HR 2.41, 95% CI 1.09–5.31; p = 0.029), UACR ≥ 300 mg/g (HR 5.14, 95% CI 1.88–14.02; p = 0.001), eGFR < 30 ml/min/1.73 m² (HR 11.58, 95% CI 4.51–29.75; p < 0.001) and DPIsUCR >1.0 g/kg·d (HR 3.53, 95% CI 1.54–8.09; p = 0.003). Notably, male patients and those with Alb < 30 g/L, UACR ≥ 300 mg/g, eGFR < 30 ml/min/1.73 m², and DPIsUCR >1.0 g/kg·d consistently exhibited poorer prognosis in both cohorts (p < 0.05). The strengthened hazard ratios (e.g., eGFR < 30 subgroup increased from HR = 5.54 to 11.58) and narrower confidence intervals post-matching suggest improved estimation precision, reinforcing these factors as robust independent prognostic markers.

    Fig. 2
    figure 2

    Kaplan-Meier survival curves for the Composite Endpoint, grouped by DPIsUCR levels. a: Kaplan-Meier curve for the Composite Endpoint within all T2DM with CKD patients. b: Kaplan-Meier curve for the Composite Endpoint within CKD 3 ~ 4 patients. Abbreviation: DPIsUCR dietary protein intake based on sUCR equation; T2DM type 2 diabetes mellitus; CKD chronic kidney disease

    Fig. 3
    figure 3

    The subgroup analysis in T2DM CKD patients with DPIsUCR equation. The subgroup analyses were conducted using a stratified Cox proportional-hazards re-gression model across various subgroups. a: Subgroup analyses of primary T2DM with CKD cohort. b: Subgroup analyses of T2DM with CKD cohort after PSM. Abbreviation: SBP systolic blood pressure, HGB hemoglobin, eGFR estimated glomerular filtration rate, DPIsUCR dietary protein intake based on sUCR equation, UA uric acid, LDLC low-density lipoprotein, HbA1c, glycated hemoglobin, UACR urine albumin to creatinine ratio; T2DM type 2 diabetes mellitus; CKD chronic kidney disease; PSM propensity score matching

    To balance the influence of time-related variables, we incorporated time-averaged parameters including TA-DPIsUCR and TA-eGFR into the analysis, as shown in Fig. 4(a-b). Subgroup analyses revealed distinct prognostic patterns across cohorts. In the original unmatched cohort, female sex demonstrated protective effects (HR 0.73, 95% CI 0.56–0.94; p = 0.017), while elevated risks were observed in subgroups with TA-eGFR 30–59 ml/min/1.73 m² (HR 2.18, 95% CI 1.50–3.15; p < 0.001) and TA-eGFR < 30 ml/min/1.73 m² (HR 12.28, 95% CI 8.65–17.45; p < 0.001). Following PSM, the risk stratification intensified significantly. The protective association with female sex became more pronounced (HR 0.29, 95% CI 0.13–0.61; p = 0.001). High-risk subgroups now included both TA-DPIsUCR and TA-eGFR categories: TA-eGFR 30–59 ml/min/1.73 m² (HR 3.09, 95% CI 1.25–7.68; p = 0.015), TA-eGFR < 30 ml/min/1.73 m² (HR 21.53, 95% CI 8.14–56.98; p < 0.001), TA-DPIsUCR 0.8–1.0 g/kg·d (HR 2.73, 95% CI 1.35–5.53; p = 0.022) and TA-DPIsUCR >1.0 g/kg·d (HR 3.03, 95% CI 1.17–7.83; p = 0.022). This matched analysis revealed a striking dose-response relationship between proteinuria severity (TA-DPIsUCR) and adverse outcomes, while confirming the critical prognostic value of sex and renal dysfunction (TA-eGFR) thresholds. The results from both the original and matched cohorts indicated that the prognosis was worse in the subgroup of males with eGFR < 30 ml/min/1.73 m², and DPIsUCR >1.0 g/kg·d.

    Results of the NHANES cohort

    Baseline data characteristics

    The flowchart of enrolled patients is detailed in Supplementary Fig. 3 to show the inclusion process before PSM. This study initially screened 101,316 patients and excluded 99,593 patients, consisting of 43,737 patients who were younger than 18 years or older than 80 years, 3,545 patients with incomplete weight and height data, and 3,399 patients with incomplete urea nitrogen or creatinine values. Additionally, 48,392 patients were excluded due to missing 24-hour dietary review data or having two dietary protein intakes at the same level, 173 patients with an eGFR < 15 ml/min/1.73 m² or who had started dialysis at enrollment, and 347 patients who died of malignant tumors. Ultimately, 1,723 patients were included in the analysis.

    Fig. 4
    figure 4

    Time-average subgroup analysis in patients with T2DM with CKD with the DPIsUCR equation. a: Time-average analyses of the primary T2DM with CKD cohort. b: Time-average analyses of the T2DM with CKD cohort after PSM. Abbreviation: TA-DPIsUCR time average dietary protein intake based on sUCR equation; TA-eGFR time average esti-mated glomerular filtration rate; T2DM type 2 diabetes mellitus; CKD chronic kidney dis-ease; PSM propensity score matching

    Participants were grouped based on their DPIsUCR levels, with 694, 811 and 218 patients in three groups respectively. After an average follow-up period of 87.63 months, a total of 489 patients reached the observation endpoint (heart diseases, cerebrovascular diseases and all-cause mortality), which included 190 patients with heart disease and 29 patients with cerebrovascular disease as the cause of death.

    PSM analysis of the NHANES cohort

    As shown in Supplementary Fig. 4, variables matched among the three dietary regimen groups included key clinical characteristics such as sex, age and baseline SCr. The balance of these characteristics across the three groups was assessed using a multi-balance test.

    After matching, a total of 390 patients were included in the final analysis. With an average follow-up period of 87.19 months, 121 patients reached the study endpoint, including 46 patients developed heart disease, 6 patients experienced cerebrovascular events, and the rest with other causes. The enrollment process is detailed in Fig. 5.

    In the original cohort, significant differences in baseline characteristics such as gender, age, and eGFR were observed among the three groups. However, after matching, these differences were balanced, as detailed in Table 2. For example, the baseline ages of the three groups were [73.00 (66.00, 78.75) vs. 72.50 (65.25, 79.00) vs. 73.00 (65.00, 80.00) years, P = 0.925], and baseline renal function (eGFR) values were [52.03 (44.62, 57.23) vs. 52.17 (42.70, 57.53) vs. 51.69 (39.69, 59.18) ml/min/1.73 m², P = 0.995]. Other baseline characteristics also showed balance.

    Table 2 Demographic and biochemical characteristics of enrolled NHANES participants before and after propensity score matching
    Fig. 5
    figure 5

    Flowchart of the NHANES enrolled participants after propensity score matching. Abbreviation: DPIsUCR dietary protein intake based on sUCR equation

    Real-world prognosis analysis of DPIsUCR equation in CKD 1 ~ 4 patients

    In the matched cohort, Kaplan-Meier survival analysis was applied to evaluate the relationship between different DPIsUCR levels and all-cause mortality. As shown in Fig. 6a, patients in the restricted protein diet group (DPIsUCR < 0.8 g/kg·d) exhibited a better survival curve compared to those in the higher protein intake group (DPIsUCR > 1.0 g/kg·d). Specifically, in patients with CKD stage 3 (Fig. 6b), the survival curve of the restricted protein group (DPIsUCR < 0.8 g/kg·d) was significantly better than that of the higher protein intake group (DPIsUCR > 1.0 g/kg·d) over time. However, in CKD patients with diabetes (Fig. 6c), although the survival curve of the restricted protein group appeared better, the difference did not reach statistical significance.

    To further validate the robustness of these findings, univariate Cox regression analysis was performed on the cohorts before and after matching as presented in Supplementary Table 2. Before matching, patients with DPIsUCR < 0.8 g/kg·d had a 63% reduction in all-cause mortality compared to those with DPIsUCR > 1.0 g/kg·d. After adjusting for confounding factors such as age, sex, smoking history, diabetes status, SBP, HbA1c, Alb, UA, CHOL and HDLC, the mortality reduction was 47% for patients with DPIsUCR < 0.8 g/kg·d compared to those with DPIsUCR > 1.0 g/kg·d.

    In the matched cohort, after correcting for variables such as age, sex, smoking history, HbA1c, eGFR, UA, and HDLC, patients with DPIsUCR < 0.8 g/kg·d had a 50% lower risk of all-cause mortality compared to those consuming more than 1.0 g/kg·d of dietary protein.

    Fig. 6
    figure 6

    The prognostic analysis of different DPI in CKD patients with DPIsUCR equation. a: Kaplan-Meier curve for the Composite Endpoint within all CKD patients. b: Kaplan-Meier curve for the Composite Endpoint within CKD stage 3 patients. c: Kaplan-Meier curve for the Composite Endpoint within DKD patients. Abbreviation: DPIsUCR dietary protein intake based on sUCR equation

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  • Shorter days ahead? Why Earth might spin faster on 3 days in July and August – Firstpost

    Shorter days ahead? Why Earth might spin faster on 3 days in July and August – Firstpost

    Should we expect shorter days soon?

    The Earth is likely to spin slightly faster in July and August, which could lead to shorter days.

    Notably, the Earth completes a little more than 365 full spins on its axis each year. That is the total number of days we have in a year.

    ALSO READ |
    Is Africa cracking open? How Earth’s ‘heartbeat’ is tearing the continent apart, forming a new ocean

    However, it was not always like this. Some studies show that in the past, Earth took between 490 and 372 days to complete one trip around the Sun.

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    So, which days in July and August might be the shortest? And what is the reason behind this change?

    Let’s take a look:

    Why and when Earth is predicted to spin faster

    A scientist has warned that Earth’s rotation is speeding up unexpectedly, with the shortest day in history possibly just weeks away.

    Graham Jones, an astrophysicist from the University of London, said the Earth’s spin may increase slightly on three specific days, July 9, July 22, and August 5, he told Daily Mail.

    The difference will be very small, measured only in milliseconds.

    On these days, the length of a day might drop by 1.30, 1.38, or 1.51 milliseconds, one after the other.

    Experts say that even a slight change can impact satellite systems, GPS accuracy, and how we keep track of time.

    The Earth is likely to spin slightly faster in July and August, which could lead to shorter days. Pixabay/Representational Image

    Leonid Zotov, a researcher at Moscow State University, said: “Nobody expected this, the cause of this acceleration is not explained.”

    Since 2020, scientists have observed the Earth turning slightly quicker than usual, but they are still unsure why this is happening.

    Earlier, the planet had been slowing down gradually, mainly due to the moon’s pull, which over time helped shape our current 24-hour days.

    Typically, the Earth takes 24 hours, or exactly 86,400 seconds, to complete one full spin, known as a solar day.

    Judah Levine, a physicist at the National Institute of Standards and Technology, told Discover Magazine in 2021, “This lack of the need for leap seconds was not predicted.”

    “The assumption was, in fact, that Earth would continue to slow down and leap seconds would continue to be needed. And so this effect, this result, is very surprising.”

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    If the Earth keeps rotating faster, timekeepers might need to make changes to official time, which could include removing a leap second for the first time ever in 2029.

    Why is Earth spinning faster?

    The Earth’s rotation is not perfectly steady. It can shift by a few milliseconds now and then.

    This happens because natural forces, such as earthquakes and ocean movements, can change the planet’s spin slightly.

    Other reasons include melting glaciers, changes in Earth’s molten core, and weather patterns like El Nino, which can either slow down or speed up rotation by small amounts.

    Scientists use atomic clocks to track these tiny changes with high precision. The recent increase in spin has caught many of them off guard.

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    According to reports, the fastest day so far was on July 5, 2024, when the Earth spun 1.66 milliseconds faster than the usual 24 hours.

    Earthquakes are also known to affect the planet’s rotation. In March 2011, a magnitude 9.0 earthquake near Japan shifted the Earth’s axis and slightly shortened the length of a day.

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    The Earth’s rotation is not perfectly steady. It can shift by a few milliseconds now and then. Pixabay/Representational Image

    Dr Richard Gross from Nasa’s Jet Propulsion Laboratory told Popular Mechanics in 2011, “Earthquakes can change the Earth’s rotation by rearranging the Earth’s mass. This is what a spinning ice skater does to make herself spin faster. She moves her arms closer to her body, she’s moving her mass closer to the axis about which she’s rotating.”

    Understanding the causes of this spin change involves looking at what’s happening inside the Earth, from moving molten layers deep in the core to powerful ocean currents and winds high in the sky.

    Earth’s interior is not solid all the way through. Its centre is made of hot, liquid metal that flows and shifts. This movement can change the planet’s balance, like a skater turning faster by pulling in their arms.

    Currents in the ocean and jet streams, fast air flows high up in the atmosphere, also move mass around, leading to small changes in the speed of Earth’s rotation.

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    Scientists are looking at all of these, the moon’s pull, movement in the core, ocean flow, and wind, to understand what’s happening.

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  • Antony Gormley’s Crosby iron men over the years

    Antony Gormley’s Crosby iron men over the years

    Silhouetted against sunsets, half-buried in sand or standing poignantly under the moonlight – Crosby Beach’s celebrated iron men sculptures have inspired visitors for two decades.

    Sir Antony Gormley’s Another Place, featuring 100 iron figures modelled on the artist’s own body, has become synonymous with the Sefton coast near Liverpool.

    Marking the work’s 20th anniversary this week, Sir Antony said: “I think it’s about life and death, love and loss, and without people reacting to it, it’s nothing.”

    Here are a selection of striking images of the artwork from over the years.

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  • OPEC+ members agree larger-than-expected oil production hike in August

    OPEC+ members agree larger-than-expected oil production hike in August

    The OPEC logo is displayed on a mobile phone screen in front of a computer screen displaying OPEC icons in Ankara, Turkey, on June 25, 2024.

    Anadolu | Anadolu | Getty Images

    Eight oil-producing nations of the OPEC+ alliance on Saturday agreed to lift their collective crude production by 548,00 barrels per day, as they continue briskly unwinding a set of voluntary supply cuts.

    This subset of the alliance — comprising heavyweight producers Russia and Saudi Arabia, alongside Algeria, Iraq, Kazakhstan, Kuwait, Oman and the United Arab Emirates — met digitally earlier in the day. They had been expected to increase their output by a smaller 411,000 barrels per day.

    In a statement, the OPEC Secretariat attributed the countries’ decision to raise August daily output by 548,000 barrels to “a steady global economic outlook and current healthy market fundamentals, as reflected in the low oil inventories.”

    The eight producers have been implementing two sets of voluntary production cuts outside of the broader OPEC+ coalition’s formal policy.

    One, totaling 1.66 million barrels per day, stays in effect until the end of next year.

    Under the second strategy, the countries reduced their production by an additional 2.2 million barrels per day until the end of the first quarter.

    They initially set out to boost their production by 137,000 barrels per day every month until September 2026, but only sustained that pace in April. The group then tripled the hike to 411,000 barrels per day in each of May, June and July — and are further accelerating the pace of their increases in August.

    Oil prices were briefly boosted in recent weeks by the seasonal summer spike in demand and the 12-day war between Israel and Iran, which threatened both Tehran’s supplies and raised concerns over potential disruptions of supplies transported through the key Strait of Hormuz.

    At the end of the Friday session, oil futures settled at $68.30 per barrel for the September-expiry Ice Brent contract and at $66.50 per barrel for front month-August Nymex WTI.

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  • Microsoft shuts its Pakistan office after 25 years, sparks economic concerns

    Microsoft shuts its Pakistan office after 25 years, sparks economic concerns

    Tech giant Microsoft has announced to shut down its limited operations in Pakistan as part of its global strategy to reduce workforce, which various stakeholders termed on Friday as a “troubling sign” for the country’s economy.

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    Microsoft, while closing its office in Pakistan on Thursday after 25 years, cited global restructuring and a shift to a cloud-based, partner-led model.

    The move came as the tech giant cut roughly 9,100 jobs worldwide (or about 4 per cent of its workforce) in its largest layoff round since 2023.

    Jawwad Rehman, former founding Country Manager of Microsoft Pakistan, urged the government and IT minister to engage with the tech giants with a bold KPI (Key Performance Indicators) driven plan.

    He said the exit reflected the current business climate. “Even global giants like Microsoft find it unsustainable to stay,” he posted on LinkedIn.

    Former Pakistan president Arif Alvi, in a post on X, also expressed concern over Microsoft shutting down operations.

    “It is a troubling sign for our economic future,” he wrote.

    He claimed Microsoft once considered Pakistan for expansion, but that instability led the company to choose Vietnam instead by late 2022.

    “The opportunity was lost,” he wrote.

    Jawwad explained that Microsoft didn’t operate a full commercial base in Pakistan, relying instead on liaison offices focused on enterprise, education, and government clients.

    Over recent years, much of that work had already shifted to local partners, while licensing and contracts were managed from its European hub in Ireland.


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  • Wallace Hartley sheet music part of Manchester Titanic exhibition

    Wallace Hartley sheet music part of Manchester Titanic exhibition

    Rare artefacts from the Titanic shipwreck including the sheet music from the ship’s band leader Wallace Hartley who died in the sinking are to go on display in Manchester.

    The RMS Titanic sank in April 1912 after it struck an iceberg on its maiden voyage from Southampton to New York killing more than 1,500 people.

    The Titanic Exhibition Manchester will open from 31 July to 24 August at Manchester Central.

    It will feature items such as the largest surviving fragment of the Aft Grand Staircase and the personal belongings of passengers and crew, including those from Mr Hartley, from Colne, Lancashire, who is said to have played on as the ship went down.

    The Titanic vessel, which was built by Liverpool-based White Star Line and was registered in Liverpool, sank within hours of hitting an iceberg and now lies 3,800m (12,500ft) down in the Atlantic Ocean.

    It remains one of the most famous shipwrecks in history that had its story turned into an Oscar-winning film.

    The exhibition tells the story of the ship from its construction in Belfast, through to its maiden voyage and tragic sinking.

    It examines the legacy left behind, including its impact on film and television.

    Dik Barton, the first British man to dive to the Titanic, is also attending the exhibition.

    He has done 22 dives to the wreck and is holding three lectures a day revealing new details about the site and what it’s like to dive 2.5 miles (4km) to the Titanic.

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