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  • The Effect of Minimal-dose S-ketamine on Opioids Consumption in Postop

    The Effect of Minimal-dose S-ketamine on Opioids Consumption in Postop

    Introduction

    Thoracic surgery is frequently associated with acute postoperative pain, with a prevalence of moderate-to-severe pain reported to be as high as 62.9%.1,2 Inadequate perioperative pain management following thoracoscopy can worsen respiratory function, potentially leading to postoperative pulmonary complications, chronic post-thoracotomy pain syndrome (CPTPS), and delayed recovery in patients.3 Among thoracic surgeries, radical resection of esophageal cancer is known to cause severe acute postoperative pain due to the extensive trauma of the procedure.

    Opioids have traditionally served as the primary treatment for moderate to severe acute postoperative pain.4 Current recommendations advocate for the implementation of multimodal analgesic regimens and non-opioid interventions to minimize perioperative opioid consumption and mitigate opioid-related adverse effects, such as nausea, vomiting, over sedation, ileus, pruritus, and respiratory depression, enhancing and expediting patients’ postoperative recovery.5

    (R,S)-ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, is a racemic mixture of equal amounts of (R)-ketamine (arketamine) and (S)-ketamine (S-ketamine).6,7 S-ketamine is used as an anesthetic in several countries, including China. The 2018 guideline “Intravenous Ketamine for Acute Pain Treatment”, jointly issued by the American Society of Regional Anesthesia (ASRA), the American Academy of Pain Medicine (AAPM) and the American Society of Anesthesiologists (ASA), advocates for integrating subanesthetic ketamine doses (not exceeding 0.35 mg/kg or 1 mg/kg/h) into postoperative PCIA for surgeries anticipating severe acute postoperative pain in patients. The guidelines suggest that subanesthetic ketamine doses could lead to a 20% reduction in opioid usage for acute postoperative pain management.8 Nevertheless, the effect of S-ketamine, which exhibits a higher affinity for NMDAR than (R,S)-ketamine and R-ketamine, on opioid consumption for managing acute postoperative pain in patients undergoing radical esophageal cancer resection remains uncertain. The study by Bornemann-Cimenti in 2016 indicated that the dosage of S-ketamine (0.015 mg/kg/h×48h) was similar to that of (R, S)-ketamine (0.25 mg/kg/h×48h) for managing acute postoperative pain.9 This study aims to investigate the effect of minimal-dose S-ketamine (0.015 mg/kg/h×48h) for acute postoperative pain management on reducing opioid consumption, enhancing analgesic quality, and facilitating postoperative recovery in patients undergoing radical esophageal cancer resection.

    Materials and Methods

    Study Design

    This randomized double-blinded controlled trial was conducted at Zhongda Hospital affiliated with Southeast University. The study protocol was approved by the Ethics Committee of Zhongda Hospital affiliated with Southeast University (No. 2022ZDSYLL138-P01) and registered in the Chinese Clinical Trial Register (ChiCTR2100048311, http://www.chictr.org.cn/). Written informed consent was obtained from all participants or their legal representatives before recruitment. This study complies with the Declaration of Helsinki and adhered to the 2010 Consolidated Standards of Reporting Trials (CONSORT).10

    Participants

    The investigators screened eligible patients the day before surgery (or on Friday if they underwent surgery the following Monday). Patients who met the following criteria were included: aged 18–80 years, ASA status I–III and were scheduled to undergo minimally invasive radical resection of esophageal cancer. Patients who met any of the following criteria were excluded: allergy to S-ketamine or oxycodone, unstable ischemic cardiac disease, increased intracranial or intraocular pressure, untreated or poorly treated hyperthyroidism, psychiatric disease, severe hepatic dysfunction (Child–Pugh grade C), renal failure (requiring renal replacement therapy), severe respiratory dysfunction (respiratory failure type I or type II), previous long-term use of analgesics, previous basic pain (chronic pain), conversion to thoracotomy, transfer to the intensive care unit (ICU), unwillingness or inability to use a PCIA device, and cognitive impairment or inability to communicate.

    Randomization and Blinding

    This study included 216 patients who underwent minimally invasive radical resection of esophageal cancer under general anesthesia. Participants were numbered sequentially based on their enrollment order. A nurse used IBM SPSS Statistics 27 to generate random numbers and randomly allocate participants to one of the two groups in a 1:1 ratio. The randomization sequence was generated and placed in sequentially numbered sealed radiopaque envelopes. Once the investigator confirmed eligibility, the envelopes were opened sequentially and participants were assigned to their respective groups by the designated nurse who performed numerical randomization. Intravenous pumps of the drugs were used by the coded PCIA device (with a fixed background infusion rate of 2 mL/h) delivered to the operating rooms by a pharmacist and were started at the end of surgery: Group E, S-ketamine 0.015 mg/kg (diluted to 96 mL with 0.9% NS); Group C, 96 mL with 0.9% NS. This study was double blinded. The patients, researchers who performed data collection and postoperative follow-up, and clinical staff were blinded to group allocation throughout the study.

    Intervention

    Intraoperative Management

    General anesthesia was standardized, and no premedication was administered. Anesthesia was induced intravenously with midazolam (0.03–0.05 mg/kg), propofol (1.5–2.5 mg/kg), sufentanil (0.3–0.5 μg/kg), and rocuronium (0.6–0.9 mg/kg). Mechanical ventilation was performed after tracheal intubation, and the respiratory rate and tidal volume were adjusted to maintain the PETCO2 at 35–45 mmHg. Intravenous Ketorolac 30 mg was administered to the patients before the surgical procedure. Anesthesia depth was adjusted by target-controlled infusion of propofol and inhalation of a sevoffurane/oxygen/air mix to maintain a bispectral index value between 40 and 60. The remifentanil infusion rate was adjusted based on the mean arterial pressure and heart rate (within 20% of the baseline values).

    Postoperative Management

    The coded PCA with a fixed background dose of 2 mL/h were started at the end of surgery: Group E, S-ketamine 0.015 mg/kg (diluted to 96 mL with 0.9% NS); Group C, 96 mL 0.9% NS. All the patients were transferred to the post-anesthesia care unit (PACU) for extubation.

    Postoperative Multimodal Analgesia

    After extubation in the PACU, a fixed anesthesiologist performed ultrasound-guided paravertebral nerve block and another PCIA device (oxycodone 50 mg diluted to 100 mL with 0.9% NS) was administered to all patients. An ultrasound-guided paravertebral nerve block was performed by a specialized anesthesiologist with expertise in acute pain management. The ultrasound probe was positioned perpendicularly to the dorsal midline at the spinous processes of the target thoracic vertebrae (T5 and T8), with the inner end of the probe aligned on the dorsal midline. The imaging demonstrated the spinous process of the target thoracic vertebra and the transverse process of the adjacent thoracic vertebra. The probe was then adjusted cephalad to avoid interference with the transverse process of the adjacent thoracic vertebra, ensuring its placement between the two transverse processes and parallel to them. The paravertebral space of the thoracic vertebrae was identified as the region enclosed by the deep portion of the articular process, approximately 1 cm lateral to it, and bounded externally by the pleura. A needle was inserted lateral to the probe, carefully avoiding contact with the pleura, and advanced into the space between the articular process and the pleura. After confirming the absence of blood or cerebrospinal fluid upon aspiration, 10 mL of 0.187% ropivacaine was administered to the paravertebral regions of the target thoracic vertebrae. Oxycodone PCIA was programmed at a background dose of 0–2 mL/h and a single bolus dose of 4 mL, followed by a 10-min interval lockout. All patients received ketorolac (30 mg) intravenously daily. How to use oxycodone PCIA, postoperative follow-up and the adjustment of the PCIA were performed by a fixed nurse and a fixed anesthesiologist: if the NRS pain scores at rest was 0, the background dose would be reduced; otherwise, if the NRS pain scores at rest was > 3, the background dose would be increased until the score was ≤ 3. If the FAS was still grade C after one bolus injection, a bolus dose would be administered again 10 min later and so on until the FAS decreased to grade A/B. The PONV was treated with intravenous tropisetron (2 mg). When the liquid in the pump box of the oxycodone PCIA was exhausted, the original concentration of the medical solution could be added under aseptic conditions. If delirium occurred, dexmedetomidine (0.5 μg/kg) was pumped intravenously within 15 minutes and then infused at a rate of 0.2 to 0.7 μg/kg/h until the symptoms were controlled.

    Outcomes

    The primary outcome was cumulative opioid consumption in the first 48 h postoperatively. The main secondary outcomes included FAS scores (after one bolus administration) at postoperative hour 12 (T3), postoperative hour 24 (T4), postoperative hour 48 (T5), postoperative hour 72 (T6), NRS pain scores (at rest and when coughing) at postoperative hour 2 (T1), postoperative hour 6 (T2), T3,T4,T5,T6, and the cumulative opioid consumption in different periods (postoperative 0–24 hours, 24–48 hours, 48–72 hours). Other pre-specified secondary outcomes included LOS scores at T2 – T6, time of first postoperative flatulation, BI, incidence of PONV, postoperative delirium, pulmonary complications and other complications, duration of chest tube use, length of postoperative hospital stay, and satisfaction of medical workers and patients. Postoperative pain was evaluated using the NRS (11- point scale: 0 [no pain], 0 < NRS < 4 [mild pain], 4 ≤ NRS < 7 [moderate pain], 7 ≤ NRS < 10 [severe pain], 10 [worst pain imaginable]). Patients regularly used an external vibration expectoration machine (one bolus administration would be given in advance) from postoperative hour 12 and FAS scores (Grade A: no limitation [pain does not limit functional activity at all]; Grade B: mild limitation [pain slightly limits functional activity]; Grade C: Severe limitation [pain severely limits functional activity]) were used to evaluate the effect. Postoperative sedation was assessed using LOS scores (Grade 0: awake and responsive; Grade 1: slightly drowsy, but easy to wake up [Grade 1S: normal sleep state]; Grade 2: frequent drowsiness, easy to wake up, but not continuously awake; Grade 3: difficult to awaken). Activities of daily living were assessed using the Barthel Index (BI), with a total score of 100 points (≥ 60 points, can take care of themselves; 41–59 points, moderate dysfunction, need assistance in daily life; 21–40 points, severe dysfunction, requiring assistance in daily life, and ≤ 20 points requiring assistance in daily life). Postoperative delirium was diagnosed based on the Intensive Care Delirium Screening Checklist (ICDSC) (total scores ≥ 4). Pulmonary complications include pulmonary infection, atelectasis, pulmonary edema and pneumothorax. Other complications include anastomotic leakage and abnormal bleeding. The satisfaction levels of the medical staff and patients were assessed using NRS scores from 0 to 10 points (the higher the score, the better the satisfaction).

    Sample Size Calculation

    Oxycodone consumption after minimally invasive radical resection of esophageal cancer in the previous year was calculated for the control group. We calculated the standard deviation (29.6 mg) and mean oxycodone consumption (66.5 mg) (postoperative 0–48 h). The guideline “Intravenous Ketamine for the treatment of Acute Pain” suggested that the addition of subanesthetic doses of ketamine can reduce opioid use by 20%.8 So the expected reduction in oxycodone consumption would be 13.3 mg (66.5 mg × 20%). With the power set at 90% and a one-sided significance level of 0.05, 172 patients were required to detect differences. Owing to the 20% dropout rate, 216 patients were enrolled in the trial.

    Statistical Analysis

    Statistical analyses were performed using a modified intention-to-treat approach, which excluded patients deemed ineligible after enrollment. All data were checked for normal distribution using the Kolmogorov–Smirnov test. Continuous variables are presented as mean (standard deviation, SD) or median (interquartile range, IQR), and Student’s t-test or Mann–Whitney U-test was performed to compare the difference between the two groups according to the Kolmogorov–Smirnov test. Categorical variables are presented as numbers (percentages) and were compared using Pearson’s χ2 test or Fisher’s exact test as appropriate.

    For the primary outcome, cumulative opioid consumption at postoperative 0–48 hours, Mann–Whitney U-tests were performed to compare the difference between the two groups and the median difference and its 95% CI were estimated using the Hodges-Lehmann estimator. Generalized estimating equations (GEEs) with robust standard error estimates were used to account for repeated measures of pain and FAS scores.

    Statistical significance was set at P < 0.05. Statistical analyses were performed using IBM SPSS version 27 or GraphPad Prism 10.0.

    Results

    Study Population

    A total of 325 patients were assessed for eligibility between January 1, 2022, and October 30, 2024. Of these, 216 were eligible and randomized. The final intention-to-treat analysis included 202 patients (Figure 1). Overall, the patient demographics and surgical and anesthetic characteristics were balanced between the groups (Table 1).

    Table 1 Demographic and Clinical Characteristics at Baseline

    Figure 1 CONSORT diagram for the study.

    Abbreviations: ICU, intensive care unit; Group E, S-ketamine group; Group C, control group.

    Primary Outcome Analysis

    The postoperative opioid consumption within 48 hours in S-ketamine group was significantly lower than those in placebo group (P <0.001) (Table 2, Figure 2), and the difference between the two groups was 40% (mean: 44.5 mg vs 74.8 mg).

    Table 2 Comparison of Oxycodone Consumption (Mg) Between the Two Groups

    Figure 2 Comparison of indicators of the analgesic efficacy between the two groups. (A). Oxycodone Consumption; (B). Probability of FAS A/B after 1 bolus; (C). NRS score for pain at Rest; (D) NRS of pain when coughing.

    Abbreviations: Group E, S-ketamine group; Group C, control group; POD 1, postoperative 0–24 h; POD 2; postoperative 24–48 hours; POD 3: postoperative 48–72 hours; T1, postoperative hour 2; T2, postoperative hour 6; T3, postoperative hour 12; T4, postoperative hour 24; T5, postoperative hour 48; T6, postoperative hour 72.

    Notes: Compared with T1 in the same group, #P <0.05; compared with Group C at the same time point, *P <0.05, **P <0.01, ***P<0.001.

    Secondary Outcomes Analyses

    The NRS pain scores at rest were all ≤ 3, and the FAS (after 1–3 bolus dose administrations) was grade A/B in both groups, which met the requirements for postoperative analgesia. At T3,T4, T5, and T6, the proportion of FAS (after one bolus dose administration) with grade A/B in group E was significantly higher than that in group C (P < 0.001, P= 0.007, P < 0.001, P < 0.001, respectively) (Table 3, Figure 2). The NRS pain scores at rest at T5 in group E were lower than those in group C (P = 0.001) and the NRS pain scores when coughing at T3 in group E were larger than those in group C (P = 0.011) with mean differences of −0.3 and 0.4 respectively (Table 3, Figure 2). The AUC of the NRS pain scores at rest in group E was smaller than that in group C within 72 hours after surgery (P = 0.027) (Table 3). Oxycodone consumption in group E was significantly lower than that in group C within 24, 24–48 and 48–72 hours after surgery (P < 0.001, P < 0.001, P < 0.001, respectively) (Table 2, Figure 2), and the differences between the two groups were 40%, 41% and 47% respectively (mean: 23.6 mg vs 39.4 mg, 21.0 mg vs 35.4 mg, 16.9 mg vs 31.8 mg).

    Table 3 Comparison of Postoperative Pain Between the Two Groups

    Safety and Other Outcomes Analyses

    The proportion of flatulation within 48 h postoperatively in group E was higher than that in group C (P = 0.029), the BI at 48 h postoperatively in group E was higher than that in group C (P = 0.008) and the postoperative hospital stay in group E was shorter than that in group C (P = 0.044) (Table 4). There was no statistically significant difference in postoperative pulmonary complications between the two groups; however, the incidence of postoperative pulmonary complications in group E (3.7%) was lower than that in group C (10.2%). The LOS scores were all grade 0 or 1 in the two groups, which met the requirements for postoperative analgesia and did not differ significantly between the two groups (Table 4). There were no significant differences in incidence of PONV, other complications, duration of chest tube placement, and satisfaction levels of medical staff and patients between two groups (Table 4).

    Table 4 Comparison of Safety and Other Outcomes Between the Two Groups

    Discussion

    The main findings of the study are as follows. First, Opioid consumption within the first 48 h postoperatively for acute pain management was significantly lower in the S-ketamine group than in the control group in patients undergoing radical resection for esophageal cancer. Second, the FAS and BI scores were notably higher in the S-ketamine group than in the control group. Moreover, there was a statistically significant difference in the NRS pain scores between the two groups of patients; however, the score differences were less than 1 point. Given that the minimum unit of the NRS score is 1 point and prior studies have demonstrated that a decrease of at least 1.3 points in the NRS pain score relative to baseline pain intensity is required for clinically meaningful pain relief, the observed differences in this study lacked clinical significance despite being statistically significant.12–14 Time to first postoperative flatulence and length of postoperative hospital stay were lower in the S-ketamine group than in the control group. There were no significant differences in the incidence of PONV, LOS, postoperative delirium, pulmonary and other complications, duration of chest tube placement, or satisfaction levels of medical staff and patients between the two groups.

    Selection of the Study Population

    The addition of subanesthetic doses of ketamine is supported by the guidelines for patients undergoing thoracic surgery expected to cause severe postoperative pain.8 Postoperative pain following thoracic surgery, particularly radical resection of esophageal cancer, is known to be severe, with incidence rates of moderate to severe pain reaching 62.9%.2 Given the high demand for analgesia observed in patients undergoing minimally invasive radical resection of esophageal cancer, often necessitating patient-controlled analgesia (PCIA) for over 72 h post-surgery, this study focused on this specific patient population to enhance postoperative pain management.

    Selection of the Primary Outcome and the Secondary Outcome FAS

    The perioperative analgesia guidelines aim to achieve postoperative pain tolerance or a pain level of NRS ≤ 3.15–17 Our department implemented artificial intelligence patient-controlled analgesia (Ai-PCA) in 2012 and established the Acute Pain Service (APS) in 2017. Due to clinical and ethical considerations, to ensure adherence to the analgesic goal, we strived for homogeneity in pain scores: NRS scores at rest were ≤ 3 and FAS levels were grade A or B. Therefore, the primary outcome of this study was opioid consumption, which served as an indirect indicator of analgesic efficacy.

    In this study, all patients achieved FAS levels of grade A/B following 1–3 bolus administrations and we chose the FAS levels obtained after one bolus administration as the secondary outcome to assess the difference in functional exercise between the two groups. Conventional clinical studies frequently integrate both S-ketamine and opioids into PCIA.18–20 Moreover, unlike typical clinical studies, we did not incorporate S-ketamine into PCIA because it would result in discrepancies in the bolus between the two groups.

    Selection of S-Ketamine Dosage

    S-ketamine, being more potent and less prone to adverse effects than racemic ketamine, is a viable alternative during the perioperative period. A recent meta-analysis by Wang et al21 indicates that intravenous S-ketamine, when used as an adjunct to general anesthesia, effectively enhanced analgesia, reduced postoperative pain intensity, and minimized opioid requirements in the short term. However, it may also increase the incidence of psychotomimetic adverse events. Notably, the risk of such adverse events is significantly higher in the intra- and postoperative group compared to the intraoperative-only group, possibly due to higher postoperative infusion rates (doses ranged from 0.075 to 0.5 mg/kg for boluses and 1.25 to 10 μg/kg/min for infusions).21 Studies by Bornemann-Cimenti9 and Zhang20 have shown that minimal-dose S-ketamine (0.015 mg/kg/h for 48 hours) yields comparable analgesic effects to conventional low-dose S-ketamine regimens, while also demonstrating similar outcomes to a placebo in terms of postoperative delirium and sedation. Therefore, in light of the literature and the outcomes of preliminary experiments, the minimum dose of S-ketamine (0.015 mg/kg/h for 48 h) was selected for this study to achieve the desired therapeutic effect while minimizing the dosage.

    Exploratory Outcomes Analyses

    Exploratory Primary Outcome Analysis

    Our findings indicate that the addition of a minimum dose of S-ketamine to postoperative analgesia reduces the postoperative opioid requirements. Our study showed an approximate 40% decrease in postoperative opioid requirements in the S-ketamine group compared to the control group, consistent with previous research and surpassing the anticipated 20% reduction, confirming the study’s statistical power to detect differences between groups.9,22

    Exploratory Main Secondary Outcomes Analyses

    Multimodal pain management, a key element in Enhanced Recovery After Surgery (ERAS) protocols, often includes the NMDA receptor antagonist ketamine because of its efficacy in reducing opioid consumption and pain levels.5,21,23,24 The primary aim of analgesia is to enhance postoperative rehabilitation, as indicated by the FAS assessment. Our findings revealed significantly improved FAS scores in the S-ketamine group compared to the control group, highlighting the superior analgesic efficacy of S-ketamine in functional exercises.

    Safety and Other Outcomes

    The time to first postoperative flatulence, bowel movements, and length of hospital stay were significantly better in the S-ketamine group than in the control group, possibly because of the reduced postoperative opioid use and enhanced mobilization. No significant differences were observed in LOS scores or postoperative delirium between the groups, consistent with previous studies.9,20 The incidence of postoperative nausea and vomiting did not differ between the groups, aligning with conflicting findings in the literature.21,25 Although a decrease in pulmonary complications was noted, it was not statistically significant, nor were other complications. Previous studies suggest that perioperative administration of S-ketamine or ketamine in various surgeries may confer anti-inflammatory and immunoprotective effects with efficacy potentially dose-dependent.26–29 Inconclusive results may be attributed to inadequate power analysis for this outcome, limiting the study’s ability to detect differences.

    Limitations

    First, continuous constant-rate intravenous infusion was selected to ensure that the hourly dosage of S-ketamine remained at its minimum level. Nonetheless, incorporating S-ketamine into the PCIA may offer greater clinical convenience. Further studies and design improvements are necessary to build this foundation. Second, this trial was conducted at a single center. Therefore, the generalizability of our findings to other patient populations remains unclear. Third, we did not design multiple dosage groups to determine the optimal dose. The minimal-dose of S-ketamine used in this protocol was based on previous studies. Given the relatively small number of patients undergoing esophageal cancer surgery, it took approximately three years to complete this study. Comparing multiple groups would have further prolonged the research period. Clinically, treatment modalities for various diseases and postoperative analgesia management are continually evolving. A protracted research timeline may introduce potential biases into the results. These limitations could be addressed through multicenter collaboration in future studies. Fourth, no quantitative indicators of hyperalgesia were used in this study. In the pilot study, von fair silk was used to measure the area of pain sensitivity. However, the patients refused because they used a band to fix their chest to relieve pain after surgery, and the process of removing the band was complicated and inconvenient. This limitation should be fully considered in future studies, and alternative methods such as the pressure pain threshold (PPT) assessment are recommended. Fifth, the sample size was calculated based on the primary outcomes. Therefore, it is highly likely that our relatively small sample size underpowered the secondary outcomes (such as the incidence of pulmonary complications and PONV). Large-scale randomized controlled trials should be conducted to address these limitations.

    Conclusion

    In conclusion, the minimum dose of S-ketamine for managing acute postoperative pain in patients undergoing radical resection of esophageal cancer leads to a 40% reduction in opioid use and promotes postoperative functional exercise and rehabilitation, which is worthy of clinical promotion.

    Data Sharing Statement

    All data generated or analyzed during this study have been included in the published article. Further inquiries regarding the datasets can be directed to the corresponding author upon reasonable request.

    Funding

    This work was supported by the Nanjing Health Science and Technology Development Special Fund Project (Grant No.: YKK21264) and Beijing Medical Award Foundation (Grant No.: YXJL-2021-0307-0737).

    Disclosure

    The authors declare no conflicts of interest in this work.

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  • Microsoft shuts down Pakistan operations after 25 years amid global restructuring and layoffs

    Microsoft shuts down Pakistan operations after 25 years amid global restructuring and layoffs

    In a move that has rattled Pakistan’s already fragile tech landscape, Microsoft has announced the closure of its local office, ending a 25-year presence in the country. The tech giant, as part of its global workforce reduction strategy, will now serve Pakistani clients remotely through its regional hubs and authorised resellers, rather than maintaining a direct presence on the ground. Microsoft confirmed the shift in a statement to TechCrunch, saying it reflects a model it already uses in various countries. The company was quick to assure that existing customer agreements and services will continue unaffected, and that the quality of support will remain consistent.

    The decision, though affecting only five employees locally, has sent shockwaves through Pakistan’s business and tech communities. These individuals were largely focused on enterprise sales of Microsoft services such as Azure and Office. Unlike in India, Microsoft never established a development or engineering base in Pakistan, limiting its footprint to liaison and sales operations. Still, the withdrawal is being seen as more symbolic than numerical, a troubling signal about Pakistan’s appeal to international tech players.

    However, the move coincides with Microsoft’s largest round of global job cuts, with over 9,000 positions recently being slashed worldwide. Pakistan’s Ministry of Information and Broadcasting has attributed the company’s exit to this wider organisational restructuring. In reality, Microsoft had already been quietly transitioning core functions such as licensing and contract management to its European hub in Ireland over the past few years.

    Former Microsoft Pakistan country head Jawwad Rehman urged the government to take proactive steps to retain and attract global tech players. “Even global giants like Microsoft find it unsustainable to stay,” he wrote in a candid LinkedIn post, calling on the IT ministry to initiate KPI-driven engagement strategies with multinational firms.

    Former President Arif Alvi also weighed in on social media, labelling Microsoft’s retreat as “a troubling sign for our economic future.” Alvi revealed that Microsoft had once considered expanding its operations in Pakistan but ultimately chose Vietnam due to the latter’s greater political and economic stability. “The opportunity was lost,” he added.

    The timing of Microsoft’s exit has raised further eyebrows, especially as it comes just days after the government announced an ambitious initiative to provide half a million young people with global IT certifications, including those from Microsoft itself. The disconnect between policy ambition and on-ground corporate confidence has laid bare the challenges facing Pakistan’s tech ecosystem.

    While Google continues to invest in local educational initiatives and is even exploring Chromebook manufacturing in Pakistan, Microsoft’s quiet withdrawal underscores a broader issue: Pakistan has yet to position itself as a serious player in the global tech outsourcing arena. In contrast to neighbouring India, which has built a thriving IT export economy, Pakistan’s tech space is often dominated by regional players such as Huawei, with global giants remaining hesitant.

    As Pakistan eyes digital transformation, Microsoft’s departure is a wake-up call, one that highlights the need for stability, clear policy direction, and stronger engagement with the global tech community.

    – Ends

    Published By:

    Unnati Gusain

    Published On:

    Jul 5, 2025

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  • Stitching Human Rights into Fashion: The Unseen Cost in Global Supply Chains

    Stitching Human Rights into Fashion: The Unseen Cost in Global Supply Chains

    Fashion, a multi-trillion-dollar business, wraps us in style and individuality, from the colorful Parisian catwalks to the clothes we wear in everyday life. Beauty and affordability come at a high price, though; under the fabric that conceals glamor stands a bitter reality, which can be summarized as many pieces of clothes are assembled by exploited hands, which are not under surveillance of buyers in the developed world. Due to the highly sophisticated, transnational supply chain network between fashionably obsessed, clothing-loving countries, modern-day human rights violations have become a thriving business, and the real, hidden price of our addiction to fast fashion has finally found its outlet.

    Human rights groups and labor activists have been highlighting vicissitudes of the gross exploitation of garment factories, especially in Southeast Asia, South Asia, and Latin America, over the past decades. The growth in the race to the bottom observed with the constant striving of big global companies to keep their production increasingly less expensive has placed the costs of cost reduction on the workers, many of whom are women and isolated groups.

    The list of abuses is disturbingly long and consistent:

    •         Poverty Wages: Garment workers get low salaries that they cannot withstand feeding or housing the family, despite living in backbreaking conditions. Such wages are usually far below the minimum living wages.

    •         Exhausting schedules and optional overtime: Twelve to fourteen hours a day, six or seven days a week, are the typical schedules, especially during the peak season. Denial of overtime working may make an employee dismissed.

    •         Unsafe Working Conditions: Factories have poor ventilation, fire escapes, and basic protective gear. A dramatic illustration that negligence has fatal consequences is the collapse of the Rana Plaza building in Bangladesh in 2013 that took away the lives of more than 1,100 garment workers.

    •         Child and Forced Labor: There is still an incidence of child labor along different points in the supply system, as witnessed in some companies picking cotton to manufacture garments. Vulnerable people are also trapped through forced labor, which is usually based on debt bondage or holding of identity papers.

    •         Restriction of Union Rights: Trying to organize and claim improved conditions, the workers often get intimidated, harassed, and even hard fired by the factory owners, often with implicit acceptance on behalf of the representatives of the brands.

    •         Gender-Based Violence and Harassment: Women comprising such a great percentage of the garment working population are more prone to sexual harassment, verbal abuse, and unfairness done to them by their supervisors.

    Global supply chains are quite complex systems, and this makes accountability extremely difficult. An individual garment can include raw materials produced in one nation, then it is spun and woven in another country, it is dyed and finished in another location, and then it is finally assembled in a fourth country. Every link introduces subcontractors, which gives brands a convenient excuse of being unaware of or declining direct responsibility for the activities on the lower levels of their supply chain.

    As Dr. Anya Sharma, a researcher of labor ethics, says, the fashion industry has crushed the tricks of staying opaque. The exploitation always occurs there, at several steps below, where things are not seen so clearly, and yet there is desperate competition for contracts to exploit people inhumanly.

    Consumers are also involved unwillingly. What people call the attractiveness of fast fashion, meaning stylish apparel at shockingly low prices, is what drives an overproduction-overconsumption paradigm. When a t-shirt is cheaper than a cup of coffee, it is a clear indication that someone somewhere is being seriously exploited.

    Nonetheless, this can be changed. Consumer awareness is rising and making brands more ethically responsible when it comes to sourcing and more transparent. At least, such movements as Fashion Revolution make consumers ask brands the question of “Who made my clothes?” and require better accountability. Some ethical fashion labels are showing that it is possible to pay good salaries and provide decent working conditions and still make a profit.

    The governments also play the pivotal role of implementing strict labor legislation, and corporations should be accountable. To develop the process of universal human rights into international norms, international collaboration is required.

    In the end, the future of fashion has a common responsibility to human dignity. As students, consumers, and people of future professions, we can insist on doing better. As we all learn to educate ourselves, to purchase ethical brands, to lobby for better regulations, and, perhaps most importantly, to buy less and buy better so that we can start to weave the fabric that puts the human right back into what we wear, no one will be taken advantage of to clothe our backs.

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  • IFSC CLIMBING WORLD CUP KRAKÓW 2025: WHAT THE ATHLETES SAID

    IFSC CLIMBING WORLD CUP KRAKÓW 2025: WHAT THE ATHLETES SAID

    The IFSC Climbing World Cup in Kraków, Poland hosted competitors from around the world at this year’s fourth Speed World Cup competition. Here’s what some of the top-performing athletes had to say following each round.

    PRE-EVENT

    Sam Watson of the USA:

    “I feel really lucky to be in Poland, it’s a really cool place and it’s my first time in the country.”

    “The venue looks amazing. The city of Krakow, walking around, it’s such a cool, old town, and this venue – the square, the backdrop, it all looks amazing.”

    Natalia Kalucka of Poland

    “To be honest I’m a little bit nervous because I want to showcase my level to my home crowd. But I think I am ready because I’ve got a lot of experience in climbing now.”

    “I think it will be crazy. I think the crowd is quite specific in Poland, but quite friendly. I think they will give a bit more support to the Polish athletes so it will be a good motivation for us Polish climbers.”

    “My main goal is to focus on my personal performance. The first part of the season was a little hard for me as I feel I did quite a few little mistakes, so I want to only show the best of me during the competition.”

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  • The Dalai Lama says he hopes to live more than 130 years ahead of 90th birthday

    The Dalai Lama says he hopes to live more than 130 years ahead of 90th birthday

    DHARAMSHALA, India (AP) — Tibetan spiritual leader the Dalai Lama said that he hopes to live until he is over 130 years old, days after he laid out a succession plan by saying he plans to reincarnate after his death.

    The Dalai Lama, who is celebrating his 90th birthday on Sunday, made these comments during a ceremony organized by his followers to offer prayers for his long life.

    “I have been able to serve the Buddha dharma and the beings of Tibet so far quite well, and I hope to live over 130 years,” the Dalai Lama told thousands of followers who had gathered Saturday in India’s northern town of Dharamshala.

    Exile Tibetans wait with ceremonial offerings for their spiritual leader the Dalai Lama at an event during which Tibetan exiles prayed for the Tibetan leader’s longevity, a day before his 90th birthday, in Dharamshala, India, Saturday, July 5, 2025.(AP Photo/Ashwini Bhatia)

    Dharamshala has been the Dalai Lama’s home in exile since 1959 after he fled Tibet in the wake of a failed uprising against Chinese rule. Since then, he has sustained Tibet’s aspirations for greater autonomy under Chinese Communist Party rule and mobilized Tibetans inside and outside China.

    On Wednesday, the Dalai Lama said that he intends to reincarnate, paving the way after his death for a successor to take on a mantle stretching back 500 years. Tibetan Buddhists believe the Dalai Lama can choose the body into which he is reincarnated.

    That announcement ended years of speculation that started when he indicated that he might be the last person to hold the role.

    The Nobel Peace Prize-winning spiritual head of Tibetan Buddhism also said that the next Dalai Lama should be found and recognized as per past Buddhist traditions, while stressing that his office will lead the search.

    China views the Dalai Lama as a separatist and has insisted that only Beijing has the authority to approve his successor.

    Tibetan spiritual leader the Dalai Lama wears a ceremonial hat as he presides over an event during which Tibetan exiles prayed for his longevity, a day before his 90th birthday, in Dharamshala, India, Saturday, July 5, 2025.(AP Photo/Ashwini Bhatia)

    Tibetan spiritual leader the Dalai Lama wears a ceremonial hat as he presides over an event during which Tibetan exiles prayed for his longevity, a day before his 90th birthday, in Dharamshala, India, Saturday, July 5, 2025.(AP Photo/Ashwini Bhatia)

    Meanwhile, the exiled Tibetan community of more than 20,000 people in Dharamshala is gearing up to celebrate the Dalai Lama’s birthday on Sunday. His followers have put up giant posters and billboards across town, as tens of thousands of people are expected to attend the event, including Buddhist leaders of various sects and followers from across the world.

    Barbara Weibel, a U.S. citizen who has been following Buddhism for more than 30 years, said she “had to be here for this.”

    “I want this long life ceremony to keep him alive as long as possible,” she said.


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  • Identifying diagnostic biomarkers for Electroacupuncture Treatment of

    Identifying diagnostic biomarkers for Electroacupuncture Treatment of

    Introduction

    Rheumatoid arthritis (RA) is the most prevalent chronic inflammatory arthritis, which can cause progressive destruction of joint cartilage.1 RA can manifest at any age, with its peak incidence typically observed in individuals aged 30–60. As a challenging chronic condition, RA significantly impairs patients’ quality of life and imposes substantial societal and economic burdens. With a prevalence of approximately 0.3% to 1%, RA is often associated with various chronic diseases, further exacerbating healthcare demands and caregiving responsibilities.2

    Currently, radical treatment for RA is limited. The therapeutic management of RA predominantly involves non-steroidal anti-inflammatory drugs (NSAIDs), conventional biological disease-modifying antirheumatic drugs (DMARDs), glucocorticoids, and other pharmacological interventions. These approaches aim to mitigate inflammation, retard disease progression, and optimize patients’ quality of life.3 However, the side effects of these drugs are controversial. Acupuncture has been practiced in Asia for over two millennia as a complementary and alternative therapeutic modality.4 Clinical studies have shown that electroacupuncture (EA) significantly relieved pain and joint swelling in RA patients and improved their quality of life without significant adverse effects.5–7 Preclinical studies have also shown that EA can significantly improve the levels of pro-inflammatory factors in the peripheral blood of RA patients to improve the internal environment for the development and progression of RA.8,9 Identifying the targeted genes underlying the therapeutic effects of EA in alleviating RA can provide critical insights for further mechanistic investigations10 and facilitate the development of standardized treatment protocols.11 However, the exact target genes of EA for RA, especially in peripheral blood, remained unidentified.

    With the development of gene microarray and bioinformatics technologies, more and more studies were focused on exploring the mechanisms of RA occurrence and key genes at the transcriptomic level.12,13 In the context of precision medicine and personalized health care, Traditional Chinese Medicine (TCM) has received increasing attention for providing personalized medical services based on TCM theories. Several studies have utilized bioinformatics analysis to identify hub targets involved in the pathogenesis of RA and validated the regulatory effects of Chinese herbal medicine on these hub targets through animal experiments. Furthermore, network pharmacology approaches were employed to elucidate the bioactive components responsible for the therapeutic efficacy.14,15 These findings provided valuable references for identifying key targets underlying EA-mediated RA alleviation. Current studies primarily aimed to elucidate how EA alleviates RA by modulating phenotype-specific genes,16,17 yet there remained a paucity of research employing bioinformatics technologies to systematically identify EA-targeted genes for RA treatment. Given the limited availability of gene targets for EA in RA, this study aimed to fill this gap by identifying the diagnostic markers for EA treatment in RA using bioinformatics tools and machine learning algorithms.

    This research retrieved mRNA expression datasets related to RA from the GEO database. The differentially expressed genes (DEGs) of RA in peripheral blood compared to normal samples and the DEGs altered by EA were obtained by differential analysis, respectively, and 26 DEGs associated with EA for RA were obtained by taking the intersection. Two diagnostic-related genes were identified by three machine learning methods, and the diagnostic efficacy of the two genes was evaluated by constructing diagnostic models. Furthermore, we determined the regulatory effects of EA on two diagnostic-related genes using qPCR.

    Materials and Methods

    Dataset Collection

    The RA relative microarray datasets were downloaded from the Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/geo/ and Table 1). Transcriptome data for GSE15573 and GSE59526 were obtained from peripheral blood. GSE15573 contained 15 normal samples and 18 RA samples, and GSE59526 contained 8 RA samples and 7 samples treated with EA. Transcriptome data for GSE17755, GSE205962, and GSE93272 were obtained from peripheral blood. GSE17755 contained 53 normal samples with 112 RA samples and GSE205962 contained 4 normal samples with 16 RA samples. To compare differences in the regulation of RA peripheral blood target genes by EA and drugs, blood samples associated with disease-modifying antirheumatic drugs (DMARDs) were downloaded from a dataset (GSE93272) containing 43 normal samples, 115 RA samples, 40 samples treated with infliximab (IFX), 37 samples treated with methotrexate (MTX), and 40 samples treated with tocilizumab (TCZ). The GSE15573 dataset was normalized using the “normalize quantiles” function in BeadStudio Software. The GSE59526 and GSE93272 datasets were normalized using the MAS 5.0 algorithm in GeneSpring Software. The GSE17755 dataset was normalized by global ratio median normalization. The GSE205962 dataset was analyzed using the RMA method with Affymetrix default analysis settings, applying global scaling as the normalization method. According to item 1 and 2 of Article 32 of the Measures for Ethical Review of Life Science and Medical Research Involving Human Subjects (dated February 18, 2023, China), this part of the bioinformatics analysis in this study was exempt from ethical approval.

    Table 1 The Details of Gene Expression Datasets

    Identification of Differentially Expressed Genes (DEGs) Related to EA in RA

    The filtering threshold was as follows: P-value < 0.05 and |log2-fold change| ≥ 0.1. DEGs related to RA were identified by comparing normal people with RA patients. DEGs related to EA treatment were identified by comparing RA patients with those who received EA treatment. By taking the intersection of DEGs related to RA and DEGs related to EA treatment, we obtained DEGs related to EA in RA.

    Identification of Diagnostic Biomarkers for RA Patients

    Diagnostic biomarkers were identified using three distinct machine learning algorithms. Specifically, the least absolute shrinkage and selection operator (LASSO) algorithm was implemented using the “glmnet” package to identify potential biomarkers, with parameters set at alpha = 1, nlambda = 100, and λmin determined as the optimal λ. LASSO effectively reduces subset size and serves as a biased estimator for handling complex collinearity. It is also efficient in selecting a limited set of predictive features. The advantages of the random forest algorithm include minimal tuning of hyperparameters and handling non-linear relationships. It also has the capability to predict continuous variables with a high degree of accuracy, sensitivity, and specificity,18 as demonstrated in this study using the “randomForest” package with nTree = 500 as the specified parameters. The top ten genes exhibiting mean decrease Gini (MDG) were identified as potential biomarkers. The support vector machine recursive feature elimination (SVM-RFE) technique is utilized to prevent overfitting and is a commonly used discriminant method for regression, classification, and pattern recognition analyses. It can improve the discriminative ability of biomarkers in classification and regression tasks, while effectively removing irrelevant features. This method was implemented using the “e1071” package, and the performance was evaluated based on the average misjudgment rates obtained from 10‐fold cross‐validations. The strategic integration of these three machine learning algorithms enhanced the confidence in selected biomarkers through complementary feature selection paradigms.

    Establishment and Evaluation of Nomogram

    The Nomogram model was developed using the “rms” package to generate calibration curves and clinical decision curves, facilitating the evaluation of clinical utility and discriminative performance of the model in the context of RA. Additionally, the “pROC” package was utilized to compute the area under the receiver operating characteristic (ROC) curve along with 95% confidence intervals (CI).

    Animals

    Eighteen specific pathogen free (SPF) male Sprague-Dawley (SD) rats aged 8 weeks weighing 160–200 g were procured from Shanghai B&K Laboratory Animals Co., Ltd. and accommodated in the Experimental Animal Center of Shanghai University of Traditional Chinese Medicine. The rats were provided with free access to food and water within a 12-hour light-dark cycle. All animal handling protocols adhered to the guidelines set forth by the National Research Council’s Guide for the Care and Use of Laboratory Animals and were sanctioned by the Experimental Animal Ethics Committee of Shanghai University of Traditional Chinese Medicine (PZSHUTCM2401080014).

    Model Establishment

    Eighteen rats were divided into three groups using random assignment (n = 6 per group): (1) Control group, (2) CFA group and (3) CFA + EA group. In the CFA and CFA + EA groups, the CFA model was prepared according to previous research. Rats were anesthetized with 2–3% isoflurane (RWD Life Science Company, Shenzhen, Guangdong, China) and 100 μL CFA suspension was injected into the right hindpaw of the rats, while saline was administered to the control group.19 Successful model induction was evidenced by the development of ipsilateral paw edema and mechanical allodynia in rats post-modeling.

    Evaluation of Pain-Response Behavior

    The paw withdrawal threshold (PWT) was assessed using an electronic von Frey anesthesiometer (IITC 2391, USA) following the methodology described by Vivancos.20 This test was conducted to observe the progression of mechanical allodynia in CFA-induced rats and to evaluate the analgesic efficacy of EA. Rats underwent testing on day 0 before the model was created, as well as on days 1, 3, and 7 following EA. Before each evaluation, the rats were acclimated in Plexiglas enclosures for a period of 30 minutes. The pressure was applied to the midplantar area of the hindpaw using a polypropylene tip connected to an electronic von Frey device. The threshold for response was automatically measured when the hindpaw reacted to the pressure. The mean value of three consecutive measurements of the PWT was calculated for each paw after recording it thrice with a 5-minute interval between each measurement.

    EA Treatment

    Stainless steel needles (0.25 × 40 mm, Huatuo) were inserted into the Kunlun (BL60) and Zusanli (ST36) acupoints on the right side to a depth of about 5 mm. A 2 Hz, 1 mA electrical signal was administered on the needles daily for 30 minutes using a stimulation device (Model G6805-2A; Shanghai Huayi Co., Shanghai, China). The treatment with EA started on the first day after the surgery and continued for 7 days. Following the final PWT assessment, the rats were anesthetized with isoflurane (5%) and blood samples were collected from the abdominal aorta into ethylenediaminetetraacetic acid (EDTA) tubes. Subsequently, the rats were euthanized via cervical dislocation, and their peripheral blood was gathered for further biological investigations.

    Real-Time Fluorescence Quantitative PCR

    The results of our bioinformatics analysis were confirmed by qPCR validation of peripheral blood samples from all rats. The primers utilized have been documented in Table 2. Total RNA was isolated with a total RNA extraction solution following the manufacturer’s protocol (Servicebio, Wuhan, China). Three individual reactions were conducted for every sample, with the average and standard deviation computed for each data point. The 2−ΔΔCT method was employed to quantify mRNA expression levels of diagnostic biomarkers, with GAPDH serving as the internal reference.

    Table 2 Specific Primer Sequences Used in qPCR

    Statistical Analysis

    The experimental data was statistically analyzed based on the GraphPad Prism software and presented as the mean ± standard deviation (SD). Statistical analysis of the control, CFA, and CFA + EA groups was performed using One-way ANOVA followed by Bonferroni post hoc tests applied for qPCR analysis, while behavioral analysis was conducted using two-way ANOVA with Bonferroni post hoc testing. A P-value of less than 0.05 was considered statistically significant for all analyses.

    Results

    Screening of DEGs Related to EA in RA

    The differential expression analysis revealed 2428 DEGs related to RA, with 1671 downregulated and 757 upregulated genes (Figure 1A and B). Similarly, a total of 486 DEGs related to EA treatment were identified, with 228 downregulated and 258 upregulated genes (Figure 1C and D). By taking the intersection of two groups of DEGs, a total of 26 DEGs related to EA in RA were identified (Figure 1E).

    Figure 1 Identification of DEGs related to EA in RA. The volcano plot (A) and heatmap (B) for DEGs related to RA. The volcano plot (C) and heatmap (D) for DEGs related to EA treatment. (E) Venn diagram of the intersection of DEGs related to RA and DEGs related to EA treatment.

    Determination of the Diagnostic Biomarkers

    As shown in Figure 2A and B, the LASSO regression algorithm identified ten potential candidate biomarkers. Then, the random forest algorithm determined the top ten candidate genes ranked by MeanDecreaseGini (Figure 2C and D). As for SVM-RFE, when the number of features was 9, the accuracy was maximized (Figure 2E), and the error was minimized (Figure 2F). After combining the results of three algorithms, two diagnostic biomarkers were identified: VEGFB and ARHGAP17 (Figure 2G).

    Figure 2 Identification of diagnostic biomarkers. The lambda values (A) and minimum (B) of diagnostic biomarkers were identified by LASSO. (C) Potential diagnostic biomarkers selection via Random Forest. (D) MeanDecreaseGini showed the rank of genes in accordance with their relative importance. (E) Accuracy and (F) error of 10-fold cross-validation in SVM-RFE algorithms, respectively. (G) The intersection of diagnostic biomarkers screened by three machine algorithms.

    Diagnostic Efficacy of Diagnostic Biomarkers

    Based on the expression of two genes, a diagnostic nomogram was constructed for RA to assess its diagnostic specificity and sensitivity (Figure 3A). ROC curves were generated to evaluate the diagnostic utility of individual genes and the nomogram. Figure 3B illustrated that VEGFB (0.819) and ARHGAP17 (0.978) had AUC values exceeding 0.75. In addition, the nomogram model (AUC = 0.981) based on two genes showed better diagnostic performance than two genes alone (Figure 3C). Based on the calibration curve analysis in Figure 3D, the nomogram model demonstrated comparable accuracy to the true positivity rate. The clinical decision curves revealed that the Nomogram model developed with two genes had a high predictive ability for RA, as the model curve outperformed the two threshold curves for benefits (Figure 3E).

    Figure 3 Construction of the nomogram model and efficacy assessment. (A) The nomogram of diagnostic biomarkers for risk prediction of RA. (B) The ROC curves of each diagnostic biomarker. (C) The ROC curve of the nomogram model. (D) The calibration curve of nomogram model prediction in RA. (E) DCA results to evaluate the clinical value of the nomogram model.

    Identification and Verification of Diagnostic Biomarkers

    The diagnostic effectiveness of two genes for RA was validated on peripheral blood samples from three external datasets with RA. The AUC values of VEGFB and ARHGAP17 were 0.692 and 0.815 in GSE17755 (Figure 4A), respectively, and the diagnostic model showed promising efficacy in RA (AUC = 0.817) (Figure 4D). Besides, the AUC values of VEGFB and ARHGAP17 genes were 0.721 and 0.767 in GSE93272 (Figure 4B), respectively, and the diagnostic model showed good efficacy in RA (AUC = 0.794) (Figure 4E). The AUC values of VEGFB and ARHGAP17 genes were 0.922 and 0.945 in GSE205962 (Figure 4C), respectively, and the diagnostic model showed good efficacy in RA (AUC = 1.000) (Figure 4F).

    Figure 4 The ROC curves of each diagnostic biomarker and the nomogram model in GSE17755 (A and D), GSE93272 (B and E) and GSE205962 (C and F).

    In addition, the diagnostic biomarkers showed differential expression in the training and validation cohorts. The expression levels of ARHGAP17 and VEGFB in the peripheral blood of patients with RA were significantly decreased in GSE15573 (Figure 5A and B), GSE17755 (Figure 5C and D), GSE93272 (Figure 5E and F), and GSE205962 (Figure 5G and H) compared to healthy individuals. Besides, EA can increase the levels of VEGFB and ARHGAP17 in the peripheral blood of RA patients (Figure 6A and B), with comparable effectiveness to DMARDs such as IFX (Figure 6C and D), MTX (Figure 6E and F), and TCZ (Figure 6G and H).

    Figure 5 Expression levels of ARHGAP17 and VEGFB in the GSE15573 (A and B), GSE17755 (C and D), GSE93272 (E and F), and GSE205962 (G and H). *p < 0.05, **p < 0.01, ***p < 0.001, compared to the Control group.

    Figure 6 Comparison of ARHGAP17 and VEGFB expression levels following treatment with EA (A and B), IFX (C and D), MTX (E and F), and TCZ (G and H). *p < 0.05, **p < 0.01, ***p < 0.001, compared to the RA group.

    EA Demonstrated Analgesic Effects in CFA-Induced Mechanical Allodynia

    Measurement of PWT in the ipsilateral hindpaws of rats showed hyperalgesia induced by CFA and antihyperalgesic effects of EA. As shown in Figure 7, the baseline values of PWT prior to injection of CFA did not exhibit significant differences across groups. Following the administration of CFA, the PWT of the CFA group and the CFA+EA group exhibited a significant decrease in comparison to the control group and the hyperalgesia endured for a minimum duration of one week. After receiving EA therapy, the rats in the CFA+EA group demonstrated a significant improvement in PWT starting from the first day as compared to the CFA group, indicating that EA significantly alleviated mechanical allodynia in CFA rats.

    Figure 7 The effects of EA on mechanical allodynia induced by CFA. ***p < 0.001 compared to the control group; ##p < 0.01, compared to the CFA group.

    The qPCR analysis showed a significant reduction in ARHGAP17 and VEGFB mRNA expression levels in the peripheral blood of the CFA group compared to the control group. Conversely, EA can significantly increase the expression of ARHGAP17 and VEGFB in the peripheral blood of CFA rats (Figure 8A and B).

    Figure 8 The effect of EA on regulating the diagnostic biomarkers. The mRNA expression of ARHGAP17 (A) and VEGFB (B) were analyzed by qPCR. ***p < 0.001 compared to the control group; ###p < 0.001 compared to the CFA group.

    Discussion

    This study identified 26 genes associated with the therapeutic effects of EA on RA. Machine learning algorithms were employed to identify two genes, ARHGAP17 and VEGFB, as potential diagnostic biomarkers, and their diagnostic efficacy was subsequently validated through the construction of a Nomogram model. Meanwhile, we demonstrated through various validation datasets that both diagnostic markers were significantly decreased in RA patients and exhibited excellent diagnostic performance. Furthermore, we found that these two biomarkers could effectively reflect the therapeutic effects of DMARDs and EA on RA, serving as prognostic indicators for evaluating treatment efficacy in RA. To further validate these findings, we established a CFA model, which revealed that the transcription levels of ARHGAP17 and VEGFB were significantly reduced in the peripheral blood of CFA-treated rats. Notably, EA therapy reversed this reduction, suggesting its potential therapeutic benefits for RA.

    Rho guanosine triphosphatases (GTPases) function as molecular switches and have been implicated in the dysregulation associated with the pathogenesis of RA.21 The enzymatic activity of Rho GTPases is stringently regulated by Rho GTPase-activating proteins (GAPs), which play a crucial role in modulating signaling accuracy and preventing aberrant activation. ARHGAP17 (Rho GTPase Activating Protein 17), also known as RICH1, belongs to the GTPase-activating proteins (GAP) family, widely expressed in human tissues, and functions as a negative regulator of GTPases. Current research on ARHGAP17 has primarily focused on its role in cancer,22 while the potential involvement of ARHGAP17 in the effects of EA remained unexplored. Notably, the Rho GTPase (RAC1) is involved in the progression of various pain conditions,23–25 and EA has been shown to alleviate pain by suppressing RAC1 expression.26 To date, no studies have established the diagnostic or therapeutic value of ARHGAP17 in RA. Interestingly, existing evidence indicated that ARHGAP17 may suppress RAC1 expression and reduce cellular apoptosis.22 Our study demonstrated that EA can reverse the decreased expression of ARHGAP17 in the peripheral blood of CFA rats, suggesting that EA may exert its anti-inflammatory and analgesic effects by promoting ARHGAP17 expression, thereby inhibiting the activation of the Rho GTPase and mitigating the progression of RA.

    Vascular endothelial growth factors (VEGFs) are the crucial molecule that promotes angiogenesis, which is a characteristic pathological feature of RA.27 Notably, a previous study has demonstrated that serum VEGF levels in RA patients correlated positively with disease severity,28 suggesting that VEGF may serve as a valuable molecular biomarker for evaluating the severity of RA. However, emerging evidence suggested that VEGF not only promoted inflammation and angiogenesis but also facilitated subchondral bone regeneration in arthritic joints.29 A preliminary study found that promoting VEGF expression within the joint can enhance lymphatic drainage, thereby reducing the severity of RA.30 As one of the subtypes of VEGF, VEGFB can be regulated by vagus nerve electrical stimulation, suppressing inflammatory responses through activation of the PI3K/AKT-FoxO3A-VEGF-A/B signaling cascade.31 This study revealed that EA can upregulate VEGFB expression in the peripheral blood of RA patients and CFA rats. This finding appeared contradictory to previous research demonstrating that EA suppressed VEGF mRNA expression in synovial tissue of adjuvant arthritis rats.32 We hypothesized that the inconsistent results may be due to differences in the regulation of VEGF subtypes by EA.

    This study was not the first to apply bioinformatics analysis to identify potential biomarkers involved in EA treatment for RA. However, compared with previous research,32 it incorporated a broader range of machine learning algorithms and validated the findings across multiple validation datasets. The present study has the following limitations: Firstly, the datasets employed in this study contained a relatively limited number of EA treatment cases. Additionally, we did not evaluate biomarker diagnostic efficacy across diverse demographic subgroups or perform batch-effect correction on the dataset. Secondly, due to experimental limitations, this study did not expand on the diagnostic efficacy of biomarkers in clinical RA patients or the regulatory effects of EA on these biomarkers. Current animal models exhibited limited capacity to fully recapitulate the complex pathogenesis of RA, thereby constraining accurate assessment of diagnostic biomarker performance and EA therapeutic efficacy across disease subtypes. Therefore, further clinical experiments are needed to extend the application of biomarkers.

    Conclusion

    The present study identified two potential diagnostic biomarkers for RA using bioinformatics and machine learning approaches, and revealed that EA modulated the expression of these genes in peripheral blood. These findings not only provided new potential biomarkers for RA diagnosis but also offered novel therapeutic targets for EA-based treatment in RA management. However, further clinical trials are necessary to validate the diagnostic efficacy of biomarkers for different populations and the regulatory effects of EA on these biomarkers.

    Abbreviations

    CFA, Complete Freund’s Adjuvant; DEGs, Differentially expressed genes; DMARDs, disease-modifying antirheumatic drugs; EA, Electroacupuncture; GEO, Gene Expression Omnibus; IFX, Infliximab; LASSO, Least absolute shrinkage and selection operator; MDG, Mean decrease Gini; MTX, Methotrexate; NSAIDs, Non-steroidal anti-inflammatory drugs; PWT, Paw withdrawal threshold; RA, Rheumatoid arthritis; ROC, Receiver operating characteristic; SVM-RFE, Support vector machine recursive feature elimination; TCM, Traditional Chinese Medicine; TCZ, Tocilizumab.

    Data Sharing Statement

    The datasets analyzed for this study can be found in the GEO (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc = GSE15573, GSE59526, GSE17755, GSE205962, and GSE93272).

    Funding

    This research was fund by Shanghai Chinese Medicine Three-Year Action Plan Project (ZY(2021-2023)-0202, ZY(2021-2023)-0502).

    Disclosure

    The authors report no conflicts of interest in this work.

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    Space burial goes wrong: Capsule with remains of 166 people and cannabis seeds crashes into Pacific ocean |

    A space capsule carrying the ashes of 166 people, along with a collection of cannabis seeds, was lost after crashing into the Pacific Ocean during reentry. The capsule, part of a mission called “Mission Possible” by German aerospace start-up The Exploration Company (TEC), launched on June 23, 2025. Its cargo, arranged through Texas-based space burial firm Celestis, successfully completed two orbits around Earth before communication was lost. While the mission aimed to be Celestis’s first to return from orbit, a reentry anomaly led to the capsule’s destruction and the scattering of its contents at sea.

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    The Nyx capsule, designed and launched by The Exploration Company, initially performed well. It powered its payloads in orbit, stabilized after launch separation, and briefly re-established communication during reentry. However, the company lost contact just minutes before splashdown. TEC confirmed the capsule crashed into the Pacific Ocean, with no materials recovered. This was Celestis’s first attempt at a return-from-orbit space burial, carrying remains of 166 individuals entrusted by families around the world. The mission also carried cannabis seeds as part of the Martian Grow project, a citizen science initiative aimed at exploring the potential of farming cannabis on Mars. TEC has only launched one other capsule prior to Nyx, and while they hailed several technical milestones, they acknowledged the risks involved and expressed a commitment to relaunching in the future.

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    Celestis co-founder Charles M. Chafer expressed disappointment and offered condolences to the families involved. He acknowledged the bravery of those who chose to participate in a first-of-its-kind return mission and emphasized the symbolic value of having their loved ones orbit Earth before their final resting place in the Pacific Ocean. Despite the tragic outcome, he noted that many milestones — launch, orbit, and controlled reentry — had been achieved. The company has reached out to affected families to offer support and discuss possible next steps. In his words, while no technical feat can replace the personal meaning behind such missions, “we remain committed to serving with transparency, compassion, and care.”


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  • Space capsule carrying ashes of 166 people meets bizarre end – MSN

    1. Space capsule carrying ashes of 166 people meets bizarre end  MSN
    2. Video Emerges of Legendary Boxer’s ICE Arrest  The Daily Beast
    3. “We Lost Bodies and Weed in Space”: Human Remains and Cannabis Crash Into Ocean After Shocking Mission Failure  Rude Baguette
    4. Space burial company loses 166 human remains in failed mission  Boing Boing
    5. 160 People Wanted to Be Buried in Space. Their Capsule Slammed Into the Ocean Instead.  Popular Mechanics

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  • Oasis comeback gig in Cardiff was dream come true for fans

    Oasis comeback gig in Cardiff was dream come true for fans

    Paul Burnell

    BBC News Manchester

    PA Media Liam Gallagher with tambourine and khaki jacket in Cardiff, He is singing into a microphone and has short dark hair.PA Media

    Fans said they could die happy now the band have played again

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    Feuding Mancunian siblings Noel and Liam Gallager walked on to stage for the first time together since 2009 and the crowd went wild.

    Lifelong fan Kevin Varley, 42, from Manchester, said: “It was brilliant – it was a real moment in time.

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    PA Media Noel Gallagher in blue denim shirt in full voice. He is singing into a microphone while playing guitar and has stylish short brown hair.PA Media

    Noel Gallagher has not enjoyed the best of relationships with his brother

    Speaking after the concert, Steve from Hertfordshire, who last saw them perform in 2006, said they had lived up to his expectations – but admitted to having had quite a few beers before the show.

    Asked for his favourite part, he said: “The beginning, the middle, and also the end.”

    “All of it was fantastic,” he said, adding: “We had a really good time, we’ve come all the way from Hertfordshire to see them in Wales.”

    Morgan, 20 and from Wales, said: “It made my life, honestly, I could get hit by a car and die, and I’d have a smile on my face.”

    Describing himself as an Oasis fan from birth, with his father encouraging him to get into them, he said: “It was unreal, being in that stadium, I’m still shaking, being here tonight is something else.”

    PA Media Oasis fans greet their heroes, A shot of the crowd with several people at the front raising their hands. Some are looking at their mobile phones.PA Media

    More than 70,000 fans joined in the massive singalong

    The band split acrimoniously in 2009 after a backstage altercation following a gig in Paris that began with Liam throwing a plum at his older brother’s head.

    In the intervening years, they engaged in a long war of words in the press, on stage and social media.

    Liam repeatedly called Noel a “massive potato” on Twitter and, more seriously, accused him of skipping the One Love concert for victims of the Manchester Arena bombing.

    Noel responded by saying Liam was a “village idiot” who “needs to see a psychiatrist”.

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