Predicting Clinically Significant Prostate Cancer Using Urine Metabolomics via Liquid Chromatography Mass Spectrometry.

PURPOSE: Biomarkers predicting clinically significant prostate cancer (sPC) before biopsy are currently lacking. This study aimed to develop a non-invasive urine test to predict sPC in at-risk men using urinary metabolomic profiles. MATERIALS AND METHODS: Urine samples from 934 at-risk subjects and 268 treatment-naïve PC patients were subjected to liquid chromatography/mass spectrophotometry (LC-MS)-based metabolomics profiling using both C18 and hydrophilic interaction liquid chromatography (HILIC) column analyses. Four models were constructed (training cohort [n=647]) and validated (validation cohort [n=344]) for different purposes. Model I differentiates PC from benign cases. Models II, III, and a Gleason score model (model GS) predict sPC that is defined as National Comprehensive Cancer Network (NCCN)-categorized favorable-intermediate risk group or higher (Model II), unfavorable-intermediate risk group or higher (Model III), and GS ≥7 PC (model GS), respectively. The metabolomic panels and predicting models were constructed using logistic regression and Akaike information criterion. RESULTS: The best metabolomic panels from the HILIC column include 25, 27, 28 and 26 metabolites in Models I, II, III, and GS, respectively, with area under the curve (AUC) values ranging between 0.82 and 0.91 in the training cohort and between 0.77 and 0.86 in the validation cohort. The combination of the metabolomic panels and five baseline clinical factors that include serum prostate-specific antigen, age, family history of PC, previously negative biopsy, and abnormal digital rectal examination results significantly increased AUCs (range 0.88-0.91). At 90% sensitivity (validation cohort), 33%, 34%, 41%, and 36% of unnecessary biopsies were avoided in Models I, II, III, and GS, respectively. The above results were successfully validated using LC-MS with the C18 column. CONCLUSIONS: Urinary metabolomic profiles with baseline clinical factors may accurately predict sPC in men with elevated risk before biopsy.

Prediction of clinically significant prostate cancer through urine metabolomic signatures: A large-scale validated study.

PURPOSE: Currently, there are no accurate markers for predicting potentially lethal prostate cancer (PC) before biopsy. This study aimed to develop urine tests to predict clinically significant PC (sPC) in men at risk. METHODS: Urine samples from 928 men, namely, 660 PC patients and 268 benign subjects, were analyzed by gas chromatography/quadrupole time-of-flight mass spectrophotometry (GC/Q-TOF MS) metabolomic profiling to construct four predictive models. Model I discriminated between PC and benign cases. Models II, III, and GS, respectively, predicted sPC in those classified as having favorable intermediate risk or higher, unfavorable intermediate risk or higher (according to the National Comprehensive Cancer Network risk groupings), and a Gleason sum (GS) of ≥ 7. Multivariable logistic regression was used to evaluate the area under the receiver operating characteristic curves (AUC). RESULTS: In Models I, II, III, and GS, the best AUCs (0.94, 0.85, 0.82, and 0.80, respectively; training cohort, N = 603) involved 26, 24, 26, and 22 metabolites, respectively. The addition of five clinical risk factors (serum prostate-specific antigen, patient age, previous negative biopsy, digital rectal examination, and family history) significantly improved the AUCs of the models (0.95, 0.92, 0.92, and 0.87, respectively). At 90% sensitivity, 48%, 47%, 50%, and 36% of unnecessary biopsies could be avoided. These models were successfully validated against an independent validation cohort (N = 325). Decision curve analysis showed a significant clinical net benefit with each combined model at low threshold probabilities. Models II and III were more robust and clinically relevant than Model GS. CONCLUSION: This urine test, which combines urine metabolic markers and clinical factors, may be used to predict sPC and thereby inform the necessity of biopsy in men with an elevated PC risk.

The AT-hook is an evolutionarily conserved auto-regulatory domain of SWI/SNF required for cell lineage priming.

The SWI/SNF ATP-dependent chromatin remodeler is a master regulator of the epigenome, controlling pluripotency and differentiation. Towards the C-terminus of the catalytic subunit of SWI/SNF is a motif called the AT-hook that is evolutionary conserved. The AT-hook is present in many chromatin modifiers and generally thought to help anchor them to DNA. We observe however that the AT-hook regulates the intrinsic DNA-stimulated ATPase activity aside from promoting SWI/SNF recruitment to DNA or nucleosomes by increasing the reaction velocity a factor of 13 with no accompanying change in substrate affinity (KM). The changes in ATP hydrolysis causes an equivalent change in nucleosome movement, confirming they are tightly coupled. The catalytic subunit's AT-hook is required in vivo for SWI/SNF remodeling activity in yeast and mouse embryonic stem cells. The AT-hook in SWI/SNF is required for transcription regulation and activation of stage-specific enhancers critical in cell lineage priming. Similarly, growth assays suggest the AT-hook is required in yeast SWI/SNF for activation of genes involved in amino acid biosynthesis and metabolizing ethanol. Our findings highlight the importance of studying SWI/SNF attenuation versus eliminating the catalytic subunit or completely shutting down its enzymatic activity.

Acupuncture in Addiction Medicine: Its History, Evidence, and Possibilities.

Substance-use disorders (SUDs) and drug addiction are not only national, but also global health concerns that have worsened during and after the COVID-19 pandemic. Acupuncture augments the endogenous opioid system and, therefore, has a theoretical basis as a treatment for opioid use disorders (OUDs). The basic science of acupuncture, its clinical research in addiction medicine, and decades of success of the National Acupuncture Detoxification Association protocol offer positive findings supporting this protocol's utility for treating SUDs. Considering the mounting opioid/substance-use concerns and deficiencies in SUD treatment availability in the United States, acupuncture can be a safe, feasible treatment option and adjunct in addiction medicine. Furthermore, large governmental agencies are lending support to acupuncture for treating acute and chronic pain, which, in turn, could translate to prevention of SUDs and addictions. This article is a narrative review of the background, the basic science and clinical research, and future direction of acupuncture in addiction medicine.

Perioperative hypertension and anesthetic management in patients undergoing resection of neuroblastoma.

INTRODUCTION: Neuroblastoma is the most common extracranial pediatric tumor, accounting for 5-8% of all childhood cancers. Neuroblastomas arise from catecholamine-secreting neural crest cells and their metabolites, vanillylmandelic acid and homovanillic acid, that are readily detected in urine. Although rarely seen in clinical practice, case reports exist documenting severe intraoperative hypertension. However, data on the incidence of intraoperative hypertension are lacking. METHODS: This report is a single-center retrospective review of patients with neuroblastoma who underwent surgical resection (n = 102) at Boston Children's Hospital from July 1, 2012 to February 28, 2021. Significant intraoperative hypertension was defined as maximum systolic blood pressure greater than 95th percentile +12 mmHg based on normative blood pressure data. Statistical analysis was performed using Fisher's exact test, Wilcoxon rank-sum test, and logistic regression. RESULTS: The overall incidence of intraoperative hypertension was 13% (n = 13/102). Higher American Society of Anesthesiologists (ASA) physical status was associated with intraoperative hypertension. Antihypertensive medications were administered intraoperatively in 9% of cases (n = 9), and the use was significantly associated with intraoperative hypertension. Of patients with preoperative urine catecholamine data (n = 82), all 10 patients who had intraoperative hypertension were noted to have elevated preoperative urine catecholamines. Intraoperative hypertension was not associated with postoperative hypertension, postoperative hypotension, or increased intensive care unit length of stay. DISCUSSION/CONCLUSION: Intraoperative hypertension in patients with neuroblastoma remains a relatively uncommon occurrence; however, it does occur at a frequency higher than previously described. While intraoperative hypertension is associated with an increased use of antihypertensive medications in the operating room, it is not associated with adverse perioperative outcomes.

Acupuncture and Global Health: Providing Medical Acupuncture Education and Service in Georgetown, Guyana.

Objective: Guyana is located on the north coast of the South American continent and is a middle-income developing country in the Caribbean. There is little educational opportunity for individuals interested in medical acupuncture. The aim of this project was to develop an introductory medical acupuncture curriculum for perioperative use. Materials and Methods: Through a carefully coordinated teaching-and-care plan, with support from physicians and various medical organizations, an educational opportunity in medical acupuncture was established at the Georgetown Public Hospital Corporation, a medical university teaching hospital in Georgetown, Guyana. The project involved development of a medical acupuncture curriculum, as well as teaching and patient care. Anesthesia staff members, resident trainees, and perioperative and pain-clinic patients participated. Results: Medical acupuncture-trained physicians were able to provide medical acupuncture education and services in a third-world country because of this project. Conclusion: This project is an ideal example of utilizing medical acupuncture for promoting global heath.

Acupuncture for pediatric pain: The trend of evidence-based research.

BACKGROUND AND AIM: Acupuncture is part of thousand years Traditional Chinese Medicine. There was promising evidence to support the efficacy of acupuncture in reducing postoperative surgery and dental pain, as well as chemotherapy-related nausea and vomiting. The US National Health Statistics Report indicated that there was significant increase in the use of acupuncture. Research on acupuncture has allowed for its integration into common adult pain practice. Acupuncture can also be utilized in pediatric patients. EXPERIMENTAL PROCEDURE: We evaluate the evidence-based acupuncture for pediatric pain research from 2008 to 2017. RESULTS: and Conclusions: Acupuncture treatment is well supported to be effective treatment for pediatric procedural pain, infantile colic, adolescent pelvic pain, and headaches under specific intervention methods. There is increasing interest in using acupuncture and related techniques for pediatric pain management. However, the evidence-based randomized controlled trials using acupuncture for pediatric pain management is very limited. Further randomized controlled trial research in pediatric pain is urgently needed.

Current Evidence for Acute Pain Management of Musculoskeletal Injuries and Postoperative Pain in Pediatric and Adolescent Athletes.

OBJECTIVE: Sports-related injuries in young athletes are increasingly prevalent with an estimated 2.6 million children and adolescents sustaining a sports-related injury annually. Acute sports-related injuries and surgical correction of sports-related injuries cause physical pain and psychological burdens on pediatric athletes and their families. This article aims to evaluate current acute pain management options in pediatric athletes and acute pain management strategies for postoperative pain after sports-related injuries. This article will also elucidate which areas of pain management for pediatric athletes are lacking evidence and help direct future clinical trials. DATA SOURCES: We conducted a literature search through PubMed and the Cochrane Central Register of Controlled Trials to provide an extensive review of initial and postoperative pain management strategies for pediatric sports-related musculoskeletal injuries. MAIN RESULTS: The current knowledge of acute pain management for initial sports-related injuries, postoperative pain management for orthopedic surgeries, as well as complementary and alternative medical therapies in pediatric sports-related injuries is presented. Studies evaluating conservative management, enteral and nonenteral medications, regional anesthesia, and complementary medical therapies are included. CONCLUSIONS: Adequate pain management is important for sports injuries in children and adolescents for emotional as well as physical healing, but a balance must be achieved to provide acceptable pain relief while minimizing opioid use and side effects from analgesic medications. More studies are needed to evaluate the efficacy of nonopioid analgesic medications and complementary therapies in pediatric patients with acute sports-related injuries.

Histone Octamer Structure Is Altered Early in ISW2 ATP-Dependent Nucleosome Remodeling.

Nucleosomes are the fundamental building blocks of chromatin that regulate DNA access and are composed of histone octamers. ATP-dependent chromatin remodelers like ISW2 regulate chromatin access by translationally moving nucleosomes to different DNA regions. We find that histone octamers are more pliable than previously assumed and distorted by ISW2 early in remodeling before DNA enters nucleosomes and the ATPase motor moves processively on nucleosomal DNA. Uncoupling the ATPase activity of ISW2 from nucleosome movement with deletion of the SANT domain from the C terminus of the Isw2 catalytic subunit traps remodeling intermediates in which the histone octamer structure is changed. We find restricting histone movement by chemical crosslinking also traps remodeling intermediates resembling those seen early in ISW2 remodeling with loss of the SANT domain. Other evidence shows histone octamers are intrinsically prone to changing their conformation and can be distorted merely by H3-H4 tetramer disulfide crosslinking.

Using Integrative Medicine in Pain Management: An Evaluation of Current Evidence.

Complementary medicine therapies are frequently used to treat pain conditions such as headaches and neck, back, and joint pain. Chronic pain, described as pain lasting longer than 3-6 months, can be a debilitating condition that has a significant socioeconomic impact. Pharmacologic approaches are often used for alleviating chronic pain, but recently there has been a reluctance to prescribe opioids for chronic noncancer pain because of concerns about tolerance, dependence, and addiction. As a result, there has been increased interest in integrative medicine strategies to help manage pain and to reduce reliance on prescription opioids to manage pain. This article offers a brief critical review of integrative medical therapies used to treat chronic pain, including nutritional supplements, yoga, relaxation, tai chi, massage, spinal manipulation, and acupuncture. The goal of this article is to identify those treatments that show evidence of efficacy and to identify gaps in the literature where additional studies and controlled trials are needed. An electronic search of the databases of PubMed, The Cochrane Library, EMBASE, PsycINFO, and Science Citation Index Expanded was conducted. Overall, weak positive evidence was found for yoga, relaxation, tai chi, massage, and manipulation. Strong evidence for acupuncture as a complementary treatment for chronic pain that has been shown to decrease the usage of opioids was found. Few studies were found in which integrative medicine approaches were used to address opioid misuse and abuse among chronic pain patients. Additional controlled trials to address the use of integrative medicine approaches in pain management are needed.

The Mi-2 homolog Mit1 actively positions nucleosomes within heterochromatin to suppress transcription.

Mit1 is the putative chromatin remodeling subunit of the fission yeast Snf2/histone deacetylase (HDAC) repressor complex (SHREC) and is known to repress transcription at regions of heterochromatin. However, how Mit1 modifies chromatin to silence transcription is largely unknown. Here we report that Mit1 mobilizes histone octamers in vitro and requires ATP hydrolysis and conserved chromatin tethering domains, including a previously unrecognized chromodomain, to remodel nucleosomes and silence transcription. Loss of Mit1 remodeling activity results in nucleosome depletion at specific DNA sequences that display low intrinsic affinity for the histone octamer, but its contribution to antagonizing RNA polymerase II (Pol II) access and transcription is not restricted to these sites. Genetic epistasis analyses demonstrate that SHREC subunits and the transcription-coupled Set2 histone methyltransferase, which is involved in suppression of cryptic transcription at actively transcribed regions, cooperate to silence heterochromatic transcripts. In addition, we have demonstrated that Mit1's remodeling activity contributes to SHREC function independently of Clr3's histone deacetylase activity on histone H3 K14. We propose that Mit1 is a chromatin remodeling factor that cooperates with the Clr3 histone deacetylase of SHREC and other chromatin modifiers to stabilize heterochromatin structure and to prevent access to the transcriptional machinery.

Nucleosome mobilization by ISW2 requires the concerted action of the ATPase and SLIDE domains.

The ISWI family of ATP-dependent chromatin remodelers represses transcription by changing nucleosome positions. ISWI regulates nucleosome positioning by requiring a minimal length of extranucleosomal DNA for moving nucleosomes. ISW2 from Saccharomyces cerevisiae, a member of the ISWI family, has a conserved domain called SLIDE (SANT-like ISWI domain) that binds to extranucleosomal DNA ~19 base pairs from the edge of nucleosomes. Loss of SLIDE binding does not perturb binding of the ATPase domain or the initial movement of DNA inside of nucleosomes. Not only is extranucleosomal DNA required to help recruit ISW2, but also the interactions of the SLIDE domain with extranucleosomal DNA are functionally required to move nucleosomes.

Acupuncture management of pain and emergence agitation in children after bilateral myringotomy and tympanostomy tube insertion.

AIM: To further investigate the effect of acupuncture in postoperative pain and emergence agitation in children undergoing bilateral myringotomy and tympanostomy tube (BMT) placement. BACKGROUND: BMT insertion surgery in children is routinely performed under general anesthesia and is associated with a high incidence of postoperative pain and agitation upon emergence from anesthesia. Various medications have been investigated to alleviate the pain and agitation, which have been accompanied by high incidence of adverse effects. In children, anecdotal reports suggest that acupuncture may offer postoperative analgesia. METHODS/MATERIALS: This prospective randomized controlled trial is to evaluate the effectiveness of acupuncture to control pain and agitation after initial bilateral myringotomy tube placement in 60 nonpremedicated children. Acupuncture was applied at points LI-4 (he gu) and HT-7 (shen men) immediately after induction of anesthesia. A single-blinded assessor evaluated postoperative pain and agitation using CHEOPS and emergence agitation scale. Pain and agitation scores were significantly lower in the acupuncture group compared to those in the control group at the time of arrival in the post anesthesia care unit and during the subsequent 30 min. RESULTS: Acupuncture treatment provided significant benefit in pain and agitation reduction. The median time to first postoperative analgesic (acetaminophen) administration was significantly shorter in the control group. The number of patients who required analgesia was considerably fewer in the acupuncture group than that in the control. No adverse effects related to acupuncture treatment were observed. CONCLUSION: Our study suggests that acupuncture therapy may be effective in diminishing both pain and emergence agitation in children after BMT insertion without adverse effects.

Changes of regional cerebral oxygen saturation during spinal anesthesia.

BACKGROUND: During spinal anesthesia, hemodynamic status is routinely monitored, but this may not give an accurate assessment of cerebral oxygenation. Cerebral oximetry, facilitated by using a near-infrared spectroscope, is a way of estimating regional cerebral oxygen saturation (SrO2). We designed this prospective clinical study to determine whether the changes in mean arterial pressure (MAP) and heart rate (HR) could predict changes in SrO2 during spinal anesthesia. METHODS: The study sample available for analysis included 45 patients, ASA class I to II, who were scheduled for elective ureteroscopic surgery requiring spinal anesthesia. Spinal anesthesia was performed with 12 mg 0.5% hyperbaric bupivacaine injected intrathecally via L3-4 or L4-5 interspace. MAP, HR, oxygen saturation by pulse oximeter, and SrO2 by near-infrared spectroscope were recorded every 2 min throughout the procedure. RESULTS: SrO2 was tested by the Shapiro-Wilk test and the results departed from the multivariate normal distribution. The method of generalized estimating equations (GEE) was then used to estimate the model. The output of the GEE analysis for the time-lag model showed that there were relationships between SrO2 and two predictors (MAP and HR) with the correction of the baseline values. All the parameters were significant at a level of 5%. The effects of the decreases of MAP and HR on SrO2 lasted continuously for at least 6 min. CONCLUSIONS: Based on the time-lag pattern between two predictors (MAP and HR) and SrO2 during spinal anesthesia, we ventured to conclude that a change in MAP or HR caused a significant decrease in SrO2. Since no patient developed any neurologic complication perioperatively, further study must be performed to elucidate the clinical importance of our findings.

Anesthesia and pain management for pediatric patients with dystrophic epidermolysis bullosa.

STUDY OBJECTIVE: To review anesthesia and pain management in pediatric patients with recessive dystrophic epidermolysis bullosa (RDEB). STUDY DESIGN: Retrospective study. SETTING: University-affiliated pediatric hospital. PATIENTS: 25 pediatric patients with RDEB had a total of 121 surgical procedures. MEASUREMENTS AND MAIN RESULTS: Pediatric patients with RDEB could have vesicles and bullae formation in the skin in response to trauma, friction, or pressure. The common surgical procedures for patients with RDEB were balloon dilation of esophageal strictures (38%), pseudosyndactyly release with or without skin graft (27%), postsurgical or skin care related dressing changes (21%), percutaneous endoscopic gastrostomy tube placement (8%), and circumcision (2%). Our anesthetic techniques included general inhalational anesthesia using mask (21%), general anesthesia using endotracheal tube (48%), and intravenous sedation (31%). No death or other major perioperative anesthetic complications occurred in these reported cases. CONCLUSIONS: Patients with RDEB can present considerable management issues for the anesthesiologists. Anesthesia and pain management can be carefully delivered with proper preoperative evaluation and preparation for pediatric patients with RDEB.

Acupuncture for persistent hiccups in a heart and lung transplant recipient.

Hiccup is an intermittent, abrupt, involuntary contraction of the diaphragm resulting in sudden inspiration abruptly opposed by the closure of the glottis. Persistent hiccups can interfere with daily activities and cause sleep disturbance and fatigue. We report a case of persistent hiccups occurring in a heart and lung transplant recipient that was successfully treated with acupuncture.