Satellite glial cells in sensory ganglia play a wider role in chronic pain via multiple mechanisms

Satellite glial cells are unique glial cells that surround the cell body of primary sensory neurons.An increasing body of evidence suggests that in the presence of inflammation and nerve damage,a significant number of satellite glial cells become activated,thus triggering a series of functional changes.This suggests that satellite glial cells are closely related to the occurrence of chronic pain.In this review,we first summarize the morphological structure,molecular markers,and physiological functions of satellite glial cells.Then,we clarify the multiple key roles of satellite glial cells in chronic pain,including gap junction hemichannel Cx43,membrane channel Pannexin1,K channel subunit 4.1,ATP,purinergic P2 receptors,and a series of additional factors and their receptors,including tumor necrosis factor,glutamate,endothelin,and bradykinin.Finally,we propose that future research should focus on the specific sorting of satellite glial cells,and identify genomic differences between physiological and pathological conditions.This review provides an important perspective for clarifying mechanisms underlying the peripheral regulation of chronic pain and will facilitate the formulation of new treatment plans for chronic pain.

Chronic venous insufficiency, could it be one of the missing pieces in the puzzle of treating pain?

Pain is a common complaint among patients seeking medical care.If left un-treated,pain can become chronic,significantly affecting patients’quality of life.An accurate diagnosis of the underlying cause of pain is crucial for effective treatment.Chronic venous insufficiency(CVI)is frequently overlooked by pain physicians.Moreover,many pain physicians lack sufficient knowledge about CVI.CVI is a common condition resulting from malfunctioning or damaged valves in lower limb veins.Symptoms of CVI,ranging from mild to severe,include pain,heaviness,fatigue,itching,swelling,skin color changes,and ulcers in the lower limbs.Recently,it has become more widely known that these symptoms can be attributed to CVI.Even slight or mild CVI can cause related symptoms.Pain physicians primarily consider neuromusculoskeletal disorders when assessing patients with leg pain,and often neglect the possibility of CVI.In clinical practice,when pain physicians encounter patients with unresolved leg pain,they must assess whether the patients exhibit symptoms of CVI and conduct tests to differ-entiate CVI from other potential causes.

Complex Regional Pain Syndrome: Outpatient Pain Management in the Chronic Setting: A Case Report

Background: Complex Regional Pain Syndrome (CRPS), previously known as reflex sympathetic dystrophy and causalgia, is a neuropathic pain condition that usually develops after an injury to an extremity. CRPS can be a debilitating condition with high levels of pain and reduced function. Aim: This case report aims to discuss the multimodal approach in the management of a patient who presented with ongoing poorly controlled pain secondary to CRPS from an injury that happened years prior. Case Presentation: A 45-year-old female was involved in a motor vehicle accident where her right leg was injured. She underwent several surgeries and developed CRPS that significantly reduced her mobility and quality of life. She presented to the pain clinic years after her initial injury and a multimodal regimen was started for her resulting in significantly improved function. Conclusion: CRPS can be a severely debilitating condition. While early diagnosis and management are important, ongoing management in the outpatient chronic pain setting is important in maintaining a good level of function.

Chronic pancreatitis:Pain and computed tomography/magnetic resonance imaging findings

Chronic pancreatitis(CP)is a fibroinflammatory disease characterized by irreversible destruction of pancreatic tissue.With the development of the disease,it may lead to exocrine and/or endocrine insufficiency.CP is one of the common diseases that cause abdominal pain,which will not get permanent spontaneous relief as the disease evolves.The American College of Gastroenterology clinical guidelines recommend computed tomography or magnetic resonance imaging as the first-line examination for the diagnosis of CP.CP common imaging findings include pancreatic atrophy,irregular dilatation of the pancreatic duct,calcification of pancreatic parenchyma,pancreatic duct stones,etc.In clinical practice,whether any correlations between CP-induced abdominal pain patterns(no pain/constant/intermittent pain)and corresponding imaging findings present are not well known.Therefore,this review aims to comprehensively sort out and analyze the relevant information by collecting lots of literature on this field,so as to construct a cross-bridge between the clinical manifestations and imaging manifestations of CP patients.Also,it provides an imaging basis and foundation for the classification and diagnosis of abdominal pain types in clinical CP patients.

Forgiveness and Chronic Pain: A Cohort Study

Background: Chronic pain is a major public health issue. It is a complex condition comprising biological, social and psychological elements, which can be challenging to manage. Forgiveness is a recognised effective intervention in various health conditions. Research has shown promising results using forgiveness as an intervention in the management of pain. This study aims to examine the relationship between forgiveness and other variables in patients suffering from chronic pain in the setting of a chronic pain clinic. Methods: Institutional ethical approval was granted for this study. Patients attending a chronic pain clinic for the first time were invited to complete a questionnaire comprising a brief socio-demographic survey and questionnaires including the Heartland Forgiveness Scale, Hospital Anxiety and Depression Scale, Pain and Anxiety Symptoms Scale and Perceived Injustice. Results: 104 adult patients were included. The mean age was 59 years. Back pain was the most common chronic pain presentation. The Heartland Forgiveness Scale (HFS) was found to have a good internal consistency among the Irish population. This study found that 55% of patients attending the pain clinic were not forgiving. Negative correlations were identified between forgiveness and pain, and forgiveness and injustice. Conclusion: The majority of patients attending a chronic pain clinic were not forgiving as measured on the HFS. There was a negative correlation between forgiveness and pain. The results have shown that forgiveness could be beneficial as a therapeutic intervention among patients attending a chronic pain clinic.

Targeting the nitric oxide/cGMP signaling pathway to treat chronic pain

Nitric oxide(NO)/cyclic guanosine 3′,5′-monophosphate(cGMP) signaling has been shown to act as a mediator involved in pain transmission and processing. In this review, we summarize and discuss the mechanisms of the NO/cGMP signaling pathway involved in chronic pain, including neuropathic pain, bone cancer pain, inflammatory pain, and morphine tolerance. The main process in the NO/cGMP signaling pathway in cells involves NO activating soluble guanylate cyclase, which leads to subsequent production of cGMP. cGMP then activates cGMP-dependent protein kinase(PKG), resulting in the activation of multiple targets such as the opening of ATP-sensitive K+ channels. The activation of NO/cGMP signaling in the spinal cord evidently induces upregulation of downstream molecules, as well as reactive astrogliosis and microglial polarization which participate in the process of chronic pain. In dorsal root ganglion neurons, natriuretic peptide binds to particulate guanylyl cyclase, generating and further activating the cGMP/PKG pathway, and it also contributes to the development of chronic pain. Upregulation of multiple receptors is involved in activation of the NO/cGMP signaling pathway in various pain models. Notably the NO/cGMP signaling pathway induces expression of downstream effectors, exerting both algesic and analgesic effects in neuropathic pain and inflammatory pain. These findings suggest that activation of NO/cGMP signaling plays a constituent role in the development of chronic pain, and this signaling pathway with dual effects is an interesting and promising target for chronic pain therapy.

High-intensity swimming alleviates nociception and neuroinflammation in a mouse model of chronic postischemia pain by activating the resolvin E1-chemerin receptor 23 axis in the spinal cord

Physical exe rcise effectively alleviates chronic pain associated with complex regional pain syndrome type-Ⅰ.However,the mechanism of exe rcise-induced analgesia has not been clarified.Recent studies have shown that the specialized pro-resolving lipid mediator resolvin E1 promotes relief of pathologic pain by binding to chemerin receptor 23 in the nervous system.However,whether the resolvin E1-chemerin receptor 23 axis is involved in exercise-induced analgesia in complex regional pain syndrome type-Ⅰ has not been demonstrated.In the present study,a mouse model of chronic post-ischemia pain was established to mimic complex regional pain syndrome type-Ⅰ and subjected to an intervention involving swimming at different intensities.Chronic pain was reduced only in mice that engaged in high-intensity swimming.The resolvin E1-chemerin receptor 23 axis was clearly downregulated in the spinal cord of mice with chronic pain,while high-intensity swimming restored expression of resolvin E1 and chemerin receptor 23.Finally,shRNA-mediated silencing of chemerin receptor 23in the spinal cord reve rsed the analgesic effect of high-intensity swimming exercise on chronic post-ischemic pain and the anti-inflammato ry pola rization of microglia in the dorsal horn of the spinal cord.These findings suggest that high-intensity swimming can decrease chronic pain via the endogenous resolvin E1-chemerin receptor 23 axis in the spinal cord.

Resolving Specific Psychological Stressors Can Instantly Reduce or Relieve Chronic Neck Pain and Upper Back Pain: Case Reports

Introduction: The goal of this study was to use a novel approach to pain relief which includes a participant using their mind to reduce or relieve their neck pain in a matter of minutes and taking continuous thermal medical imaging scans during the process to capture any concurrent temperature changes at the location of the self-reported pain. Previous studies using multidisciplinary approaches have shown that it is possible for a person to achieve a moderate reduction in pain over a period of time (typically two or more months). However, in this innovative study, the goal was to demonstrate rapid pain relief (in a matter of minutes) using only the mind. Case report: For this study, six subjects were selected, all of whom were experiencing long-term chronic neck pain. The subjects consisted of five adult females and one adult male. Several of the subjects also had pain that radiated into their upper back region. Each subject participated in one talk therapy session during which the subject’s neck was actively scanned by a thermal imaging (TI) camera that was programmed to take a new thermal image every thirty (30) seconds. The goal of the talk therapy session was to create a strong emotional shift by encouraging the subject to let go of negative emotions and replace buried painful feelings with feelings of positive expectation and optimism. Then, as the subject created this emotional shift, the goal was to observe if this change affected the subject’s self-reported physical pain, as well as noting any visible effects in thermal images. Results: All six subjects reported that they were able to relieve some or all of their pain by the end of the talk therapy session. As they did, there was simultaneously a significant decrease in temperature recorded on the TI images in the corresponding location in their neck and upper back region. This suggested that the pain relief the subjects reported was not merely “mind over matter”, since there were marked physiological changes taking place. Discussion and Conclusion: It’s worth noting that three of the subjects had moments during their talk therapy session where they thought about a specific painful memory that increased their negative emotions. At that moment, their self-reported pain also increased, and simultaneously, the infrared camera detected an increase in temperature in the corresponding location where the subjects reported increased pain. Subsequently, when the subjects were able to change the painful memory and once again move towards feelings of optimism, they reported pain relief, and simultaneously, the TI camera reported a decrease in temperature. Neither this potential outcome nor any other potential outcome was discussed with the subjects before or during the session. This research shows that talk therapy may be used as a new therapeutic option for people not only with neck pain, but possibly other types of pain, and that under certain circumstances, the results can be rapid.

Protocol for the development of clinical guidelines for the management of chronic primary pain

Introduction Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage.In 2018,the World Health Organization(WHO)revised the International Classification of Diseases,11th Revision(ICD-11)to include chronic pain as an independent disease for the first time(MG30.0).1 At the same time,the ICD-11 also developed new classifications for chronic pain,including chronic primary pain(CPP),chronic cancer-related pain,chronic post-surgical or post-traumatic pain,chronic secondary musculoskeletal pain,chronic secondary visceral pain.

Non-pharmacological pain palliation methods in chronic pancreatitis

Chronic pancreatitis(CP)is a condition characterized by persistent and often severe pain resulting from the inflammatory disease of the pancreas.While pharmacological treatments play a significant role in palliative pain management,some patients require non-pharmacological methods.This review article focuses on non-pharmacological approaches used to alleviate pain in CP.The article examines non-pharmacological palliation options,including surgery,endoscopic approaches,neurostimulation techniques,acupuncture,and other alternative medicine methods.The effectiveness of each method is evaluated,taking into consideration patient compliance and side effects.Additionally,this article emphasizes the importance of personalized pain management in CP and underscores the need for a multidisciplinary approach.It aims to summarize the existing knowledge on the use of non-pharmacological palliation methods to improve the quality of life for patients with CP.

Virtual Reality as an Adjunct to Ketamine Infusion Therapy Increases Patient Satisfaction in the Management of Chronic Pain and Depression: A Retrospective Pilot Study

The management of patients with concomitant chronic pain (CP) and Major Depressive Disorder (MDD) remains challenging for clinicians. Current chronic pharmacologic management is often unsuccessful, or has intolerable side effects to the patients. While not restricted to patients with chronic pain, these patients are often diagnosed with depression, presenting with symptoms such as poor mood, anhedonia, and altered cognitive processes. It is estimated that a substantial proportion of treated patients do not derive a substantive benefit from traditional pharmacological treatments for depression. The present study involved a retrospective review of cases, exploring the patient-reported satisfaction with and tolerability of a novel use of virtual reality (VR), coined KVR, as an adjunct to intravenous ketamine infusion therapies. Specifically, the ketamine-virtual reality protocol was employed as a potential adjunctive intervention for patients suffering from chronic pain and depression. Visual Analog Scores (VAS) associated with pain were significantly lower on the third than on the first assessment day. Montgomery-?sberg Depression Rating Scale (MADRS) scores improved following infusion and across days (i.e., sessions). Lastly, 2/3 of patients preferred the use of VR with their ketamine infusion. The results are considered in terms of implementing prospective studies to examine whether the combination therapies have a synergistic benefit and the nature and magnitude of clinically meaningful treatment effects, if any.

Efficacy of Low Dose Naltrexone on Pain Reduction in Chronic Pain Syndromes: A Meta Analysis

Chronic pain is a multifaceted debilitating experience often associated with significant physical and emotional burden. Low dose naltrexone (LDN) has gained attention in recent years for its potential utility in the management of fibromyalgia, irritable bowel syndrome, multiple sclerosis, and painful diabetic neuropathy. LDN’s analgesic effects have been associated with its ability to increase the production of endorphins while reducing the production of tumor necrosis factor-alpha, interleukin-6, reactive oxygen species and nitric oxide. This meta-analysis aims to systematically review and synthesize the available evidence on efficacy of LDN as an analgesic in pain syndromes, with a focus on chronic (neuro) inflammatory diseases. The goal is to provide clinicians with a more comprehensive estimate of the effectiveness of LDN as a non-opioid option for managing chronic pain and guide future research in the area. Thirteen randomized control trials, published from 1990 to 2022, were selected for the analysis that satisfied inclusion criteria. The overall effects in these studies were calculated using the standardized mean difference (SMD) between the LDN and placebo groups. We found an overall SMD of -10.77 (95% CI: -13.96 to -7.58) with a p-value of 0.002. This indicated that the LDN group experienced a statistically significant reduction in pain compared to placebo. This meta-analysis provides evidence for the potential efficacy of low dose naltrexone in reducing pain and enhancing analgesia in various pain syndromes. LDN may be a useful treatment option for patients suffering from chronic pain, particularly with fibromyalgia, multiple sclerosis, or diabetic neuropathy. However, further research is needed to confirm the efficacy and safety of low dose naltrexone for chronic pain conditions, especially with larger sample sizes, standardized dosing regimens and treatment durations.

Efficacy and safety of thermobalancing therapy with Dr Allen’s Device for chronic low back pain:A randomised controlled trial

BACKGROUND Lumbar disc herniation and non-specific low back pain are common conditions that seriously affect patients’health-related quality of life(HRQoL).Although empirical evidence has demonstrated that novel Thermobalancing therapy and Dr Allen’s Device can relieve chronic low back pain,there have been no randomised controlled trials for these indications.AIM To evaluate the efficacy of Dr Allen’s Device in lumbar disc herniation(LDH)and non-specific low back pain(NSLBP).METHODS A randomised clinical trial was conducted investigating 55 patients with chronic low back pain due to LDH(n=28)or NSLBP(n=27),out of which 15 were randomly assigned to the control group and 40 were assigned to the treatment group.The intervention was treatment with Dr Allen’s Device for 3 mo.Changes in HRQoL were assessed using the Numerical Pain Rating Scale and the Japanese Orthopedic Association Back Pain Questionnaire.RESULTS Thermobalancing therapy with Dr Allen’s Device showed a significant reduction in pain in the treatment group(P<0.001),with no recorded adverse effects.Both pain assessment scales showed a significant improvement in patients’perception of pain indicating improvement in HRQoL.CONCLUSION The out-of-hospital use of Thermobalancing therapy with Dr Allen’s Device for Low Back Treatment relieves chronic low back pain significantly and without adverse effects,improves the level of activity and HRQoL among patients with LDH and NSLBP.This study demonstrates the importance of this safe first-line therapy that can be used for effective at-home management of chronic low back pain.

Protocol for lower back pain management: Insights from the French healthcare system

In this editorial we comment on the article published in a recent issue of the World Journal of Clinical Cases.This article described a novel ultrasound-guided lateral recess block approach in treating a patient with lateral recess stenosis.The impact of spinal pain-related disability extends significantly,causing substantial human suffering and medical costs.Each county has its preferred treatment strategies for spinal pain.Here,we explore the lower back pain(LBP)treatment algorithm recommended in France.The treatment algorithm for LBP recommended by the French National Authority for Health emphasizes early patient activity and minimal medication use.It encourages the continuation of daily activities,limits excessive medication and spinal injections,and incorporates psychological assessments and non-pharmacological therapies for chronic cases.However,the algorithm may not aggressively address acute pain in the early stages,potentially delaying relief and increasing the risk of chronicity.Additionally,the recommended infiltrations primarily involve caudal epidural steroid injections,with limited consideration for other injection procedures,such as transforaminal or interlaminar epidural steroid injections.The fixed follow-up timeline may not accommodate patients who do not respond to initial treatment or experience intense pain,potentially delaying the exploration of alternative therapies.Despite these limitations,understanding the strengths and weaknesses of the French approach could inform adaptations in LBP treatment strategies globally,potentially enhancing patient outcomes and satisfaction across diverse healthcare systems.

Galvanic Skin Response—Extinction Biofeedback Training for Psychogenic Abdominal Pain: A Validation Protocol

Abdominal and pelvic pain of psychogenic origin is a widespread, disabling, difficult to identify, and often inadequately treated medical condition. This condition is often associated with poor quality of life due to high pain interference with daily activities. Cognitive behavioral psychological therapy and neuromodulation with biofeedback are validated therapies for the treatment of this condition. Aim of the present research work is the validation of a therapeutic protocol that involves the use of both techniques in combination. 20 patients diagnosed with psychogenic abdominal pain, of both sexes, aged between 18 and 60 years who had not benefited from pharmacological therapies were enrolled. 10 patients were randomly assigned to the control group (psychological treatment only), another 10 patients were assigned to the study group (neuromodulation with biofeedback-Galvanic skin response-extinction in combination with psychological therapy). For both groups, the pain score, interference of pain with daily living activities, pain relief, and the share of anxiety associated with the pain condition were evaluated (pre- and post-treatment). The patients who underwent the combined treatment achieved statistically significant better scores than patients in the control group, respectively −4.9 ± 0.9 vs −1.0 ± 0.4 for Pain;−5.1 ± 1.1 vs −0.9 ± 0.3 for Interference with life;−7.2 ± 3.7 vs −2.2 ± 2.1 for HAMA;4.6 ± 1.2 vs 1.1 ± 0.6 for Relief.

Biofeedback therapy for chronic pelvic pain syndrome

<abstract>Aim: To evaluate the efficacy of biofeedback therapy in patients with chronic pelvic pain syndrome (CPPS). Methods: From November 2001 to April 2002, patients visiting the Urological Outpatient Clinic of this Hospital were evaluated by means of the National Institute of Health Chronic Prostatitis Symptom Index (NIH-CPSI) and classified by the NIH classification standard. Sixty-two patients of CPPS category Ⅲwere involved in this study. All patients had been treated by conventional approaches such as antibiotics and alpha-blockers for more than half a year without any improvement. The expressed prostatic secretion results were as follows: WBC 5 to 9/high power field, lipid +-+++and bacterial culture negative. Their NIH-CPSI were 12-40. All the 62 cases complained of micturitional irritation (frequency, urgency, splitted stream and sense of residual urine), 32 cases, of pain or discomfort at the testicular, penile, scrotal, pelvic or rectal region and 13 cases, of white secretion-dripping. The patients were treated by the Urostym Biofeedback equipment (Laborie Co., Canada) 5 times a week for 2 weeks with a stimulus intensity of 15 mA-23 mA and duration of 20 minutes. Results: Sixty patients were significantly improved or cured, while no significant improvement in the remaining 2. No apparent side effect was observed. The NIH-CPSI dropped to 6 to 14 with an average reduction of 21 (P<0.01). In the 60 improved cases, pain was relieved after 2-3 treatment courses and other symptoms disappeared after 4-5 courses. Conclusion: Biofeedback therapy is a safe and effective treatment for CPPS. Large randomized clinical trials are needed to confirm its efficacy and to explore the mechanism of action.

Pain and chronic pancreatitis: A complex interplay of multiple mechanisms

Despite multiple theories on the pathogenesis of pain in chronic pancreatitis,no uniform and consistently successful treatment strategy exists and abdominal pain still remains the dominating symptom for most patients and a major challenge for clinicians.Traditional theories focussed on a mechanical cause of pain related to anatomical changes and evidence of increased ductal and interstitial pressures.These observations form the basis for surgical and endoscopic drainage procedures,but the outcome is variable and often unsatisfactory.This underscores the fact that other factors must contribute to pathogenesis of pain,and has shifted the focus towards a more complex neurobiological understanding of pain generation.Amongst other explanations for pain,experimental and human studies have provided evidence that pain perception at the peripheral level and central pain processing of the nociceptive information is altered in patients with chronic pancreatitis,and resembles that seen in neuropathic and chronic pain disorders.However,pain due to e.g.,complications to the disease and adverse effects to treatment must not be overlooked as an additional source of pain.This review outlines the current theories on pain generation in chronic pancreatitis which is crucial in order to understand the complexity and limitations of current therapeutic approaches.Furthermore,it may also serve as an inspiration for further research and development of methods that can evaluate the relative contribution and interplay of different pain mechanisms in the individual patients,before they are subjected to more or less empirical treatment.

Differences in brain structure in patients with distinct sites of chronic pain:A voxel-based morphometric analysis

A reduction in gray matter volume is common in patients with chronic back pain, and different types of pain are associated with gray matter abnormalities in distinct brain regions. To examine differ- ences in brain morphology in patients with low back pain or neck and upper back pain, we investi- gated changes in gray matter volume in chronic back pain patients having different sites of pain using voxel-based morphometry. A reduction in cortical gray matter volume was found primarily in the left postcentral gyrus and in the left precuneus and bilateral cuneal cortex of patients with low back pain. In these patients, there was an increase in subcortical gray matter volume in the bilateral putamen and accumbens, right pallidum, right caudate nucleus, and left amygdala. In upper back pain patients, reduced cortical gray matter volume was found in the left precentral and left postcen- tral cortices. Our findings suggest that regional gray matter volume abnormalities in low back pain patients are more extensive than in upper back pain patients. Subcortical gray matter volume in- creases are found only in patients with low back pain.

Characterisation of the bacterial community in expressed prostatic secretions from patients with chronic prostatitis/chronic pelvic pain syndrome and infertile men： a preliminary investigation

The expressed prostatic secretions （EPSs） of men with chronic prostatitis/chronic pelvic pain syndrome （CP/CPPS）, infertile men and normal men were subjected to microbiological study. EPSs were collected from the subjects, which included 26 normal men, 11 infertile patients and 51 CP/CPPS patients. DNA was extracted from each specimen, and the V3 regions of the 16S rRNA genes were amplified using universal bacterial primers. The results showed that the EPS 16S rRNA gene-positive rate in the CP/CPPS and infertile patients was much higher than in the normal men, but without any difference among the three patient groups. The denaturing gradient gel electrophoresis （DGGE） method was used to characterize the EPS bacterial community structure of the prostate fluid from patients with CP/CPPS or infertility issues. Principal component analysis （PCA） and partial least squares （PLS） analyses of PCR-DGGE profiles revealed that the EPS bacterial community structure differed among the three groups. Three bands were identified as the key factors responsible for the discrepancy between CP/CPPS patients and infertile patients （P〈O.05）. Two bands were identified as priority factors in the discrepancy of category IliA and category IIIB prostatitis patients （P〈O.05）. According to this research, the ecological balance of the prostate and low urethra tract, when considered as a microenvironment, might play an important role in the maintenance of a healthy male reproductive tract.

Current trends in the diagnosis and management of post-herniorraphy chronic groin pain

Inguinodynia(chronic groin pain) is one of the recognised complications of the commonly performed Lichtenstein mesh inguinal hernia repair.This has major impact on quality of life in a significant proportion of patients.The pain is classif ied as neuropathic and nonneuropathic related to nerve damage and to the mesh,respectively.Correct diagnosis of this problem is relatively difficult.A thorough history and clinical examination are essential,as is a good knowledge of the groin nerve distribution.In spite of the common nature of the problem,the literature evidence is limited.In this paper we discuss the diagnostic tools and treatment options,both non-surgical and surgical.In addition,we discuss the criteria for surgical intervention and its optimal timing.